Abstract:

The present invention relates to a compound which is
N-(4-{4-[(6-butyl-8-quinolinyl)oxy]-1-piperidinyl}butyl)ethanesulfonamide
##STR00001##
and salts thereof, processes for its preparation, to compositions
containing it and to its use in the treatment of various diseases, such
as allergic rhinitis.

Claims:

1. A compound which is
N-(4-{4-[(6-butyl-8-quinolinyl)oxy]-1-piperidinyl}butyl)ethanesulfonamide
##STR00075## or a salt thereof.

2. A compound according to claim 1, in the form of the free base.

3. A compound according to claim 1, or a pharmaceutically acceptable salt
thereof.

4. A compound according to claim 1, in the form of a dihydrochloride salt.

5. A composition which comprises a compound which is
N-(4-{4-[(6-butyl-8-quinolinyl)oxy]-1-piperidinyl}butyl)ethanesulfonamide
##STR00076## or a pharmaceutically acceptable salt thereof, and one or
more pharmaceutically acceptable carriers and/or excipients.

6. A composition according to claim 5 in which the compound is in the form
of the free base.

7. A composition according to claim 5 in which the compound is in the form
of a dihydrochloride salt.

8. A composition according to any of claims 5 to 7, wherein said
composition is suitable for intranasal delivery.

9. A combination comprising a compound which is
N-(4-{4-[(6-butyl-8-quinolinyl)oxy]-1-piperidinyl}butyl)ethanesulfonamide
##STR00077## or a pharmaceutically acceptable salt thereof, and one or
more other therapeutic agents.

10. A combination according to claim 9, in which the compound is in the
form of the free base.

11. A combination according to claim 9 in which the compound is in the
form of a dihydrochloride salt.

12. A combination according to any of claims 9 to 11, in which said one or
more therapeutic agents is a corticosteroid.

13. A combination according to any of claims 9 to 11, in which said one or
more therapeutic agents is fluticasone furoate
(6.alpha.,9.alpha.-difluoro-17.alpha.-[(2-furanylcarbonyl)oxy]-11.beta.-h-
ydroxy-16.alpha.-methyl-3-oxo-androsta-1,4-diene-17.beta.-carbothioic acid
S-fluoromethyl ester).

14. A method for the treatment of inflammatory and/or allergic diseases of
the respiratory tract which comprises administering to a patient in need
thereof an effective amount of a compound which is
N-(4-{4-[(6-butyl-8-quinolinyl)oxy]-1-piperidinyl}butyl)ethanesulfonamide
##STR00078## or a pharmaceutically acceptable salt thereof.

15. A method according to claim 14 in which the compound is in the form of
the free base.

16. A method according to claim 14 in which the compound is in the form of
a dihydrochloride salt.

17. A method according to any of claims 14 to 16, wherein the disease is
allergic rhinitis.

18. A method according to any of claims 14 to 16, wherein the compound is
administered intranasally.

Description:

[0001]The present invention relates to a class of compounds which are
quinolinyloxypiperidine and pyrrolidine derivatives, processes for their
preparation, pharmaceutical compositions containing them and to their use
in the treatment of various diseases, in particular inflammatory and/or
allergic diseases of the respiratory tract.

[0002]Allergic rhinitis (seasonal and perennial), pulmonary inflammation
and congestion are medical conditions that are often associated with
other conditions such as asthma and chronic obstructive pulmonary disease
(COPD). In general, these conditions are mediated, at least in part, by
inflammation associated with the release of histamine from various cells,
in particular mast cells.

[0003]Allergic rhinitis, also known as `hay fever` affects a large
proportion of the population worldwide. There are two types of allergic
rhinitis, seasonal and perennial. The clinical symptoms of seasonal
allergic rhinitis typically include nasal itching and irritation,
sneezing and watery rhinorrhea, which is often accompanied by nasal
congestion. The clinical symptoms of perennial allergic rhinitis are
similar, except that nasal blockage may be more pronounced. Either type
of allergic rhinitis may also cause other symptoms, such as itching of
the throat and/or eyes, epiphora and oedema around the eyes. The symptoms
of allergic rhinitis may vary in intensity from the nuisance level to
debilitating.

[0004]Allergic rhinitis and other allergic conditions are associated with
the release of histamine from various cell types, but particularly mast
cells. The physiological effects of histamine are classically mediated by
three receptor subtypes, termed H1, H2 and H3. H1 receptors are widely
distributed throughout the CNS and periphery, and are involved in
wakefulness and acute inflammation. H2 receptors mediate gastric acid
secretion in response to histamine. H3 receptors are present on the nerve
endings in both the CNS and periphery and mediate inhibition of
neurotransmitter release [Hill et al., Pharmacol. Rev., 49:253-278,
(1997)]. A fourth member of the histamine receptor family has been
identified, termed the H4 receptor [Hough, Mol. Pharmacol., 59:415-419,
(2001)]. Whilst the distribution of the H4 receptor appears to be
restricted to cells of the immune and inflammatory systems, a
physiological role for this receptor remains to be identified.

[0005]The activation of H1 receptors in blood vessels and nerve endings
are responsible for many of the symptoms of allergic rhinitis, which
include itching, sneezing, and the production of watery rhinorrhea. Oral
antihistamine compounds which are selective H1 receptor antagonists, such
as chlorphenyramine, cetirizine, desloratidine and fexofenadine are
effective in treating the itching, sneezing and rhinorrhea associated
with allergic rhinitis. Intranasal antihistamines which are selective H1
receptor antagonists, such azelastine and levocabastine, are thought to
have similar therapeutic effects to their oral counterparts. However,
such compounds generally require twice daily administration and may still
cause sedatation despite their local application.

[0006]A class of compounds have been identified as H1 receptor
antagonists.

[0007]Thus the present invention provides a compound of formula (I)

##STR00002##

whereinR1 represents straight chain C1-6alkyl;a represents 1 or
2;R2 represents --C1-6alkylene-R3-R4, in which the
alkylene is straight chain and is optionally substituted by one
C1-3alkyl group, or R2 represents a saturated 5 to 7 membered
ring containing one SO2 group;R3 represents --SO2--,
--N(R5)SO2--, --SO2N(R6)-- or
--N(R7)C(O)N(R8)--;R4 represents --C1-6alkyl,
--C5-7cycloalkyl optionally substituted by one or two C1-3alkyl
groups, --C1-3alkyleneC5-7cycloalkyl in which the
C5-7cycloalkyl is optionally substituted by one or two
C1-3alkyl groups, -aryl optionally substituted by one or two
substituents independently selected from halogen, C1-3alkyl,
trifluoromethyl, or cyano groups, or --C1-3alkylene-aryl optionally
substituted by one or two substituents independently selected from
halogen, C1-3alkyl, trifluoromethyl, or cyano groups;R5,
R6, R7 and R8 each independently represent hydrogen or
C1-6alkyl;or together R6 and R4 represent a saturated 5 to
7 membered ring, optionally containing one --O--, --S--, --NH--, or
--N(CH3)-- group;or together R3 and R4 represent a
saturated 5 to 7 membered ring, optionally containing one --O--, --S--,
--NH--, or --N(CH3)-- group;or a salt thereof.

[0008]The compounds of the invention may be expected to be useful in the
treatment of various diseases in particular inflammatory and/or allergic
diseases, such as inflammatory and/or allergic diseases of the
respiratory tract (for example allergic rhinitis) that are associated
with the release of histamine from cells such as mast cells. Further,
preferred compounds show an improved profile, in that they possess one or
more of the following properties:

[0009]Compounds having such a profile may be particularly suitable for
intranasal delivery, and/or capable of once daily administration and/or
further may have an improved side effect profile compared with other
existing therapies.

[0010]By `selectivity` it is meant that the compounds may be more potent
at the H1 receptor than at other receptors, particularly the H3 receptor
and/or the hERG receptor. The activity at the H1 receptor may be at least
about 10 fold greater (e.g. about 100 fold greater) than activity at the
H3 receptor.

[0011]In one embodiment, R4 represents --C1-6alkyl,
--C5-7cycloalkyl optionally substituted by one or two C1-3alkyl
groups, --C1-3alkyleneC5-7cycloalkyl in which the
C5-7cycloalkyl is optionally substituted by one or two
C1-3alkyl groups, -aryl optionally substituted by one or two
substituents independently selected from halogen, C1-3alkyl,
trifluoromethyl, or cyano groups, or --C1-3alkylene-aryl optionally
substituted on aryl by one or two substituents independently selected
from halogen, C1-3alkyl, trifluoromethyl, or cyano groups.

[0012]In one embodiment, R1 represents straight chain C1-6alkyl;

a represents 1 or 2;R2 represents
--C1-6alkylene-R3-R4, in which the alkylene is straight
chain and is optionally substituted by one C1-3alkyl group, or
R2 represents a saturated 5 to 7 membered ring containing one
SO2 group;R3 represents --SO2--, --N(R5)SO2--,
--SO2N(R6)-- or --N(R7)C(O)N(R8)--;R4 represents
--C1-6alkyl, --C5-7cycloalkyl optionally substituted by one or
two C1-3alkyl groups, --C1-3alkyleneC5-7cycloalkyl in
which the C5-7cycloalkyl is optionally substituted by one or two
C1-3alkyl groups, -aryl optionally substituted by one or two
substituents independently selected from halogen, C1-3alkyl,
trifluoromethyl, or cyano groups, or --C1-3alkylene-aryl optionally
substituted by one or two substituents independently selected from
halogen, C1-3alkyl, trifluoromethyl, or cyano groups;R5,
R6, R7 and R3 each independently represent hydrogen or
C1-6alkyl; or a salt thereof.

[0016]In another embodiment, R2 represents
--C2-5alkylene-R3-R4, in which the alkylene is straight
chain and is optionally substituted by one C1-3alkyl (e.g. methyl)
group, or R2 represents a saturated five membered ring containing
one SO2 group.

[0017]In another embodiment, R2 represents
--C2-5alkylene-R3-R4 (e.g.
--C2-4alkylene-R3-R4), in which the alkylene is straight
chain and is optionally substituted by one C1-3alkyl (e.g. methyl)
group.

[0032]In another embodiment, there is provided a compound which is
6-butyl-8-({1-[3-(ethylsulfonyl)propyl]-4-piperidinyl}oxy)quinoline, or a
salt thereof, such as a pharmaceutically acceptable salt thereof.

[0033]In another embodiment, there is provided a compound which is
N-(4-{4-[(6-butyl-8-quinolinyl)oxy]-1-piperidinyl}butyl)ethanesulfonamide-
, or a salt thereof, such as a pharmaceutically acceptable salt thereof.

[0034]In another embodiment, there is provided a compound which is
N-(4-{4-[(6-butyl-8-quinolinyl)oxy]-1-piperidinyl}butyl)ethanesulfonamide-
, in the form of the free base.

[0035]In another embodiment, there is provided a compound which is
N-(4-{4-[(6-butyl-8-quinolinyl)oxy]-1-piperidinyl}butyl)ethanesulfonamide-
, in the form of a dihydrochloride salt.

[0036]In another embodiment, there is provided a compound which is
N-(4-{4-[(6-butyl-8-quinolinyl)oxy]-1-piperidinyl}butyl)ethanesulfonamide-
, dihydrochloride salt, polymorphic form 1.

[0037]In another embodiment, there is provided a compound of formula (I)
as defined above with the proviso that the compound is not
6-butyl-8-({1-[3-(ethylsulfonyl)propyl]-4-piperidinyl}oxy)quinoline, or a
salt thereof, such as a pharmaceutically acceptable salt thereof.

[0038]In another embodiment, there is provided a compound of formula (I)
as defined above with the proviso that the compound is not
N-(4-{4-[(6-butyl-8-quinolinyl)oxy]-1-piperidinyl}butyl)ethanesulfonamide-
, or a salt thereof, such as a pharmaceutically acceptable salt thereof.

[0039]In another embodiment, there is provided a compound of formula (I)
as defined above with the proviso that the compound is not
6-butyl-8-({1-[3-(ethylsulfonyl)propyl]-4-piperidinyl}oxy)quinoline or
N-(4-{4-[(6-butyl-8-quinolinyl)oxy]-1-piperidinyl}butyl)ethane
sulfonamide, or salts thereof, such as pharmaceutically acceptable salts
thereof.

[0040]Representative compounds of formula (I) include the compounds of
Examples 1 to 36 and individual isomers thereof, in the form of a free
base, or as salts thereof, such as pharmaceutically acceptable salts
thereof.

[0041]It is to be understood that the invention includes all possible
combinations of groups and substituents described herein.

[0042]C1-6alkyl, whether alone or as part of another group, and
unless otherwise stated, may be straight chain or branched.
C1-3alkyl shall be interpreted similarly. Representative examples
include, but are not limited to methyl, ethyl, n-propyl, iso-propyl,
n-butyl, sec-butyl, iso-butyl, t-butyl, n-pentyl, neo-pentyl and n-hexyl.

[0044]As defined herein, the term "aryl" includes single and fused
aromatic rings. Representative examples of aryl groups include, but are
not limited to phenyl, indenyl, anthrancenyl and naphthyl. Aryl is
intended to denote all isomers thereof (i.e. all possible points of
attachment to the aryl ring). A representative aryl group is phenyl.

[0045]As defined herein, the term "C5-7cycloalkyl" refers to a
non-aromatic cyclic hydrocarbon ring having from five to seven carbon
atoms. Examples of such ring systems include cyclopentyl, cyclohexyl and
cycloheptyl.

[0046]The term "halogen" is used herein to describe, unless otherwise
stated, a group selected from fluorine, chlorine, bromine or iodine,
particularly fluorine and chlorine.

[0047]It is to be understood that the present invention covers compounds
of formula (I) as the free base and as salts thereof, for example as a
pharmaceutically acceptable salt.

[0048]It is to be further understood that references hereinafter to
compounds of the invention or to compounds of formula (I) mean a compound
of formula (I) as the free base, or as a salt.

[0049]The compounds of formula (I) may be in the form of and/or may be
administered as a pharmaceutically acceptable salt. For a review on
suitable salts see Berge et al., J. Pharm. Sci., 1977, 66, 1-19. Suitable
pharmaceutically acceptable salts include acid addition salts. As used
herein, the term "pharmaceutically acceptable salt", means any
pharmaceutically acceptable salt of a compound of formula (I), which upon
administration to the recipient is capable of providing (directly or
indirectly) a compound of formula (I), or an active metabolite or residue
thereof.

[0050]Typically, a pharmaceutically acceptable salt may be readily
prepared by using a desired acid as appropriate. The salt may precipitate
from solution and be collected by filtration or may be recovered by
evaporation of the solvent.

[0052]Compounds of formula (I) in which R3 represents
--NR5SO2-- or --SO2NR6-- may form base addition
salts. Suitable pharmaceutically acceptable base salts include ammonium
salts, alkali metal salts such as those of sodium and potassium, alkaline
earth metal salts such as those of calcium and magnesium, and salts with
organic bases whose pKa is >13.

[0053]Other non-pharmaceutically acceptable salts, e.g. oxalates or
trifluoroacetates, may be used, for example in the isolation of the
compounds of formula (I), and are included within the scope of this
invention.

[0054]Particular salts of
N-(4-{4-[(6-butyl-8-quinolinyl)oxy]-1-piperidinyl}butyl)ethanesulfonamide
include naphthalene disulfonate salts, such as a 2,6- or a
1,5-naphthalene disulfonate salt, e.g. a 1,5-naphthalene disulfonate
salt. Another particular salt is the dihydrochloride salt.

[0055]The invention includes within its scope all possible stoichiometric
and non-stoichiometric forms of the salts of the compounds of formula
(I).

[0056]It will be appreciated that many organic compounds can form
complexes with solvents in which they are reacted or from which they are
precipitated or crystallized. These complexes are known as "solvates".
For example, a complex with water is known as a "hydrate". Solvents with
high boiling points and/or solvents which are capable of forming hydrogen
bonds such as water, xylene, N-methylpyrrolidinone, methanol and ethanol
may be used to form solvates. Methods for identification of solvates
include, but are not limited to, NMR and microanalysis. Solvates of the
compounds of formula (I) are within the scope of the invention.

[0057]The compounds of formula (I) may be in a crystalline or amorphous
state, which are included in the scope of the present invention.
Furthermore, if crystalline, the compounds of formula (I) may exist in
one or more polymorphic forms, which are included in the scope of the
present invention. The most thermodynamically stable polymorphic form, at
room temperature, of compounds of formula (I) is of particular interest.

[0059]It will be appreciated that the compounds of formula (I) may possess
one or more asymmetric carbon atoms so that optical isomers e.g.
enantiomers or diastereoisomers may be formed. The present invention
encompasses optical isomers of the compounds of formula (I) whether as
individual isomers isolated such as to be substantially free of the other
isomer (i.e. pure) or as mixtures thereof (e.g. racemates and racemic
mixtures). An individual isomer isolated such as to be substantially free
of the other isomer (i.e. pure) may be isolated such that less than about
10%, particularly less than about 1%, for example less than about 0.1% of
the other isomer is present.

[0060]Further, it will be appreciated that the R and S enantiomers may be
isolated from the racemate by conventional resolution methods such as
preparative HPLC involving a chiral stationary phase, by resolution using
fractional crystallisation of a salt of the free base with a chiral acid,
by chemical conversion to a diastereoisomer using a chiral auxiliary
followed by chromatographic separation of the isomers and then removal of
the chiral auxiliary and regeneration of the pure enantiomer, or by
asymmetric synthesis.

[0061]Certain compounds of formula (I) may exist in one of several
tautomeric forms. It will be understood that the present invention
encompasses tautomers of the compounds of formula (I) whether as
individual tautomers or as mixtures thereof.

[0062]It will be appreciated from the foregoing that included within the
scope of the invention are solvates, hydrates, optical isomers, tautomers
and polymorphic forms of the compounds of formula (I) and salts thereof.

[0063]There is also provided processes for the preparation of compounds of
formula (I) or salts thereof.

[0064]For the avoidance of doubt, throughout the process section, unless
otherwise stated, (CH2)n corresponds to the C1-6alkylene
defined in R2 in the compounds of formula (I), and thus may be
optionally substituted by one C1-3alkyl group.

[0065]According to a first process, A, a compound of formula (I) in which
R3 represents --SO2-- may be prepared by reacting a compound of
formula (II)

##STR00003##

with a compound of formula (III)

##STR00004##

wherein R1, a and R4 are as defined hereinabove, n represents 1
to 6, (CH2)n may be optionally substituted by one
C1-3alkyl group, and X represents a suitable leaving group such as
chlorine, bromine, tosylate or mesylate.

[0066]The reaction may typically be carried out in a suitable solvent,
such as N,N'-dimethylformamide (DMF), optionally using an appropriate
activating agent, e.g. sodium iodide, with a suitable base, such as
sodium bicarbonate (sodium hydrogen carbonate) or potassium carbonate.
The reaction is typically heated, for example using a microwave oven at a
temperature of about 100 to 150° C. for an appropriate time, such
as about 15 to 30 min. Alternatively, the reaction may be heated using
conventional methods for longer periods of time, such as for several
hours or overnight, as appropriate.

[0067]Compounds of formula (II) may be prepared according to Scheme 1
below.

[0069]Compounds of formula (III) in which X represents tosylate or
mesylate may be prepared according to Scheme 4.

##STR00005##

wherein R1 and a are as defined hereinabove, and Boc represents
tert-butoxycarbonyl.

[0070]Reagents and Conditions: i) suitable acid e.g. concentrated
sulphuric acid, appropriate solvent such as water, sodium
3-nitrobenzenesulfonate (commercially available, for example, from
Aldrich), appropriate elevated temperature such as from about 110 to
140° C.; ii) Suzuki reaction using a suitable solvent such as DMF
and/or tetrahydrofuran (THF), suitable base e.g. potassium carbonate,
appropriate catalyst for example [1,1'-bis(diphenylphosphino) ferrocene
palladium (II)]chloride, at an elevated temperature such as from about 70
to 80° C. (for example using microwave radiation); iii) suitable
solvent such as N-methylpyrrolidinone (NMP), appropriate base e.g. sodium
tert-butoxide, at an elevated temperature for example from about 130 to
150° C.; iv) deprotection using a suitable acid e.g.
trifluoracetic acid (TFA) or hydrogen chloride in a suitable solvent such
as dichloromethane (DCM), dioxane, iso-propylalcohol or toluene at room
temperature.

[0071]Alternatively, step ii) in Scheme 1 may be carried out using
9-borabicyclo[3.3.1]nonane and an appropriate olefin to make a boron
compound (equivalent to compound (XV)) in situ. The reaction is typically
carried out in a suitable solvent such as THF with an appropriate
catalyst e.g. 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II).
The reaction is carried out in a manner similar to that described by S.
Potuzak and D. S. Tan, Tetrahedron Lett., 45:1797-1801, (2004). Olefins
are commercially available, for example, from Aldrich and include ethene,
1-propene, 1-butene, 1-pentene and 1-hexene.

[0072]The compound of formula (XII), 4-bromo-2-fluoroaniline is
commercially available, for example, from Aldrich.

[0074]The compounds of formula (XV) are commercially available, for
example from Aldrich, and include trimethylboron, triethylborane and
tributylborane.

[0075]Compounds of formula (XVII) are commercially available, for example
from Aldrich and include N-tert-butoxycarbonyl-(R)-(-)-3-pyrrolidinol,
N-tert-butoxycarbonyl-(S)-(+)-3-pyrrolidinol and tert-butyl
4-hydroxy-1-piperidinecarboxylate.

[0076]Compounds of formula (XVIII) may also be prepared according to
Scheme 2 below.

##STR00006##

wherein R1 and a are as defined hereinabove and Boc represents
tert-butoxycarbonyl.

[0077]Reagents and Conditions: i) suitable acid e.g. concentrated
sulphuric acid, appropriate solvent such as water, sodium
3-nitrobenzenesulfonate (commercially available, for example, from
Aldrich), appropriate elevated temperature such as from about 110 to
140° C.; ii) suitable solvent such as NMP, appropriate base e.g.
sodium tert-butoxide, at an appropriate elevated temperature for example
from about 130 to 150° C.; iii) suitable solvent such as THF:NMP
(10:1) at an appropriate lowered temperature e.g. from about 0 to
5° C., using a suitable catalyst for example iron (III)
acetylacetonate, preferably in an inert, water-free atmosphere.

[0078]Alternatively, step (iii) of Scheme 2 may be performed before step
(ii) of Scheme 2, thereby first forming a compound of formula (XVI), and
subsequently a compound of formula (XVIII).

[0079]The compound of formula (XIX), 4-chloro-2-fluoroaniline, is
commercially available, for example, from Aldrich.

wherein R4 is as defined hereinabove, n represents 1 to 6 and
(CH2)n may be optionally substituted by one C1-3alkyl
group.

[0082]Reagents and Conditions: i) suitable solvent such as DMF, at an
elevated temperature such as from about 60 to 90° C.; ii)
appropriate base e.g. triethylamine, in a suitable solvent for example
DCM, methanesulfonylchloride (commercially available, for example, from
Aldrich) and optionally in the presence of additional chloride ions e.g.
lithium chloride or n-butylammonium chloride; iii) suitable solvent such
as DCM, appropriate oxidising agent e.g. m-chloroperbenzoic acid
(commercially available, for example, from Aldrich); iv) appropriate
solvent such as ethanol or DMF, optionally at an appropriate elevated
temperature e.g. from about 60 to 80° C., followed by treatment
with an appropriate oxidising agent e.g. m-chloroperbenzoic acid in a
suitable solvent e.g. DCM; v) suitable solvent such as DMF at an
appropriate elevated temperature e.g. from about 60 to 80° C.

[0085]Compounds of formula (XXIV) may also be prepared in situ, by the
addition of a suitable base, such as sodium hydride to a solution of the
corresponding thiol in a suitable solvent, such as DMF. The suspension
may be left for an appropriate amount of time, e.g. about 15 min, before
continuing with the reactions described in Scheme 3.

[0087]Compounds of formula (XXV) may be prepared as described in Scheme 3,
or may also be commercially available, for example, from TCI-Europe
and/or Alfa Aesar and/or Aldrich, and include 2-(ethylthio)ethanol,
2-(iso-butylthio)ethanol, 4-(methylthio)-1-butanol,
3-(methylthio)-1-hexanol, 2-hydroxyethyl benzyl sulphide, 2-hydroxyethyl
n-pentyl sulphide, 4-chlorobenzyl 2-hydroxyethyl sulphide and
3-(methylthio)-1-propanol.

[0088]Compounds of formula (XXVI) are also commercially available, for
example, from Acros and/or Aldrich, and include 2-chloroethyl ethyl
sulphide and 1-{[(2-chloroethyl)sulfonyl]methyl}benzene .

[0093]Compounds of formula (XXIV) may also be prepared in situ, by the
addition of a suitable base, such as sodium hydride to a solution of the
corresponding thiol in a suitable solvent, such as DMF. The suspension
may be left for an appropriate amount of time, e.g. about 15 min, before
continuing with the reactions described in Scheme 4.

[0094]Compounds of formula (XXXI) are commercially available, for example,
from Aldrich, and include ethylene di(p-toluenesulfonate),
(S)-(-)-1,2-propanediol di-p-tosylate, 1,3-propanediol di-p-tosylate and
1,4-butanediol dimethanesulfonate. Alternatively, compounds of formula
(XXXI) may be prepared by methods well known to those skilled in the art,
by activation of the corresponding diol. The reaction may typically be
carried out using a suitable activating agent such as methanesulfonyl
chloride, or p-toluenesulfonyl chloride in a suitable solvent such as DCM
or pyridine. Diols corresponding to compounds of formula (XXXI) are
commercially available, for example, from Aldrich, and include ethylene
glycol, 1,2-butanediol, 1,3-propanediol, 1,3-butanediol, 1,4-butanediol,
1,4-pentanediol, 1,5-pentanediol, 1,5-hexanediol,
3-methyl-1,5-pentanediol and 1,6-hexanediol.

[0095]Compounds of formula (XXXII) are commercially available, for
example, from Aldrich and/or Alfa Aesar, and include
2-(methylsulfonyl)ethanol and 2-(ethanesulfonyl)ethanol.

[0096]In an alternative preparation, the compounds of formula (XXV) which
are HO--(CH2)2CH(Y)SR4 may be prepared according to Scheme
5 below:

##STR00009##

wherein R4 is as defined hereinabove and Y represents hydrogen or
C1-3alkyl.

[0097]Reagents and Conditions: i) suitable solvent such as DMF; ii)
suitable solvent such as THF, appropriate reducing agent e.g. lithium
aluminium hydride solution in ether, suitable lowered temperature such as
from about 0 to 5° C.

[0100]According to a second process, B, a compound of formula (I) in which
R2 represents a saturated 5 to 7 membered ring containing one
SO2 group or R2 represents ethylene-SO2--R4 may be
prepared by reacting a compound of formula (II)

##STR00010##

with a compound of formula (IV) or (IVa)

##STR00011##

wherein R1, a and R4 are as defined hereinabove and m represents
1 to 3.

[0101]The reaction may typically be carried out in a suitable solvent,
such as THF or DMF. Optionally, an appropriate base may be added, for
example sodium bicarbonate. The reaction is typically heated for example
using a microwave oven at a suitable temperature from about 100 to
150° C. for an appropriate time, such as about 15 to 30 min.
Alternatively, the heating may be conducted using conventional methods at
a suitable elevated temperature, such as from about 70 to 90° C.
for longer periods of time, e.g. about 2 to 3 hours or overnight.

[0102]Compounds of formula (II) may be prepared according to Scheme 1
above.

[0103]Compounds of formula (IV) may be commercially available or may be
prepared according to methods disclosed herein. 2,3-dihydrothiophene
1,1-dioxide is commercially available, for example, from AKOS.
3,4-dihydro-2H-thiopyran 1,1-dioxide may be prepared according to the
methods disclosed by X-F. Ren, E. Turos, C. H. Lake and M. R. Churchill,
J. Org. Chem., 60:6468-6483, (1995), see page 6483.
2,3,4,5-tetrahydrothiepin 1,1-dioxide may be prepared according to the
methods disclosed by B. F. Bonini, M. Comes-Franchini, M. Fochi, G.
Mazzanti, A. Ricci, Tetrahedron, 52:4803-4816, (1996), see compound 12.

[0104]Compounds of formula (IVa) are commercially available, for example,
from Aldrich, and include methyl vinyl sulfone, ethyl vinyl sulfone and
phenyl vinyl sulfone.

[0105]According to a third process, C, a compound of formula (I) in which
R3 represents --N(R5)SO2-- may be prepared by reacting a
compound of formula (V)

##STR00012##

with a compound of formula (VI)

##STR00013##

wherein R1, a, R4 and R5 are as defined hereinabove, n
represents 1 to 6 and (CH2)n may be optionally substituted by
one C1-3alkyl group.

[0106]The reaction may typically be carried out using a suitable solvent
such as DCM with a suitable base e.g. triethylamine.

[0107]Compounds of formula (V) may be prepared according to the following
reaction schemes (Schemes 6, 6a and 7).

wherein R1, a and R5 are as defined hereinabove, and X
represents a suitable leaving group such as chlorine, broming or iodine.

[0109]Reagents and Conditions: i) suitable solvent such as 2-butanone,
appropriate base e.g. potassium carbonate, at an elevated temperature
such as from about 70 to 90° C.; ii) suitable solvent such as
ethanol, hydrazine or hydrazine monohydrate, at an elevated temperature
such as from about 70 to 90° C.; iii) 1 equivalent of R5-X
(XXXVIIa), in an appropriate solvent such as DMF, suitable base such as
triethylamine or sodium hydride, optionally with an activating agent such
as sodium iodide; or reductive amination using R5═O (XXXVIIb),
in a suitable solvent e.g. DMF, suitable reducing agent such as sodium
triacetoxyborohydride.

wherein R1 and a are as defined hereinabove, n represents 2 to 6 and
Ra represents C1-6alkyl.

[0113]Reagents and Conditions: i) 2-benzofuran-1,3-dione (commercially
available, for example, from Aldrich) in a suitable solvent such as
toluene; ii) suitable solvent such as toluene, appropriate base e.g.
triethylamine; iii) suitable solvent such as DMF, appropriate base e.g.
DIPEA and/or tributylammonium iodide, optionally with an appropriate
activating agent e.g. sodium iodide, optionally at an elevated
temperature such as from about 70 to 90° C.; iv) suitable solvent
such as ethanol, hydrazine or hydrazine monohydrate, at an elevated
temperature such as from about 70 to 90° C.

[0114]The compounds of formula (XXXVa), are commercially available, for
example from Aldrich.

wherein R1, a and R5 are as defined hereinabove, X represents a
suitable leaving group such as chlorine, bromine or iodine, n represents
1 to 6 and (CH2)n may be optionally substituted by one
C1-3alkyl group.

[0116]Reagents and Conditions: i) suitable solvent such as 2-butanone,
appropriate base e.g. potassium carbonate, at an elevated temperature
such as from about 70 to 90° C.; ii) deprotection using a suitable
acid such as hydrogen chloride or TFA in a suitable solvent e.g. dioxane
or DCM; iii) 1 equivalent of R5-X (XXXVIIa), in an appropriate
solvent such as DMF, suitable base such as triethylamine or sodium
hydride, optionally with an activating agent such as sodium iodide; or
reductive amination using R5═O (XXXVIIb), in a suitable solvent
e.g. DMF, suitable reducing agent such as sodium triacetoxyborohydride.

[0119]According to a fourth process, D, a compound of formula (I) in which
R3 represents --N(R5)SO2-- may be prepared by reacting a
compound of formula (II)

##STR00017##

with a compound of formula (VII)

##STR00018##

wherein R1, a, R4 and R5 are as defined hereinabove, n
represents 1 to 6, (CH2)n may be optionally substituted by one
C1-3alkyl group, and X represents a suitable leaving group such as
chlorine, bromine, tosylate or mesylate.

[0120]The reaction may typically be carried out using a suitable base such
as sodium hydrogen carbonate, with an appropriate activating agent e.g.
sodium iodide, in a suitable solvent such as DMF. The reaction is
typically heated for example, using a microwave oven at an appropriate
elevated temperature for example from about 140 to 160° C., for
about 10 to 30 minutes, as appropriate. Alternatively, heating may be
with conventional apparatus, at elevated temperatures for example from
about 50 to 70° C., for about 3 hours to overnight, as
appropriate.

[0121]Compounds of formula (II) may be prepared according to Scheme 1
above.

[0122]Compounds of formula (VII) in which X represents chlorine or bromine
are commercially available, for example, from Apollo, and include
N-(2-bromoethyl)-4-chlorobenzene-1-sulfonamide,
N-(2-bromoethyl)-4-fluorobenzene-1-sulphonamide,
N-(2-bromoethyl)-3-(trifluoromethyl)benzene-1-sulphonamide,
N-(2-bromoethyl)-2,4-dichlorobenzene sulfonamide and
4-Bromo-N-(3-chloropropyl)benzene sulphonamide.

[0123]Compounds of formula (VII) in which X represents mesylate or
tosylate may be prepared according to Scheme 8 below.

##STR00019##

wherein R4 and R5 are as defined hereinabove, n represents 1 to
6 and (CH2)n may be optionally substituted by one
C1-3alkyl group.

[0124]Reagents and Conditions: i) suitable solvent such as DCM,
appropriate base e.g. triethylamine, at a lowered temperature such as
from about 0° C. to room temperature.

[0125]Compounds of formula (VI) are commercially available, see above
(described after process C).

[0127]According to a fifth process, E, a compound of formula (I) in which
R3 represents --SO2N(R6)-- may be prepared by reacting a
compound of formula (II)

##STR00020##

with a compound of formula (VIII)

##STR00021##

wherein R1, a, R4 and R6 are as defined hereinabove, n
represents 1 to 6, (CH2)n may be optionally substituted by one
C1-3alkyl group, and X represents a suitable leaving group such as
chlorine or bromine.

[0128]The reaction may typically be carried out using a suitable solvent
such as DMF with an appropriate activating agent for example, sodium
iodide, with a suitable base, e.g. potassium carbonate. The reaction is
usually heated using conventional apparatus, at an appropriate elevated
temperature for example from about 50 to 70° C., for about 3 hours
to overnight, as appropriate.

[0129]Compounds of formula (II) may be prepared according to Scheme 1
above.

[0130]Compounds of formula (VIII) may be prepared according to Scheme 9
below.

##STR00022##

wherein R4 and R6 are as defined hereinabove, n represents 1 to
6 and (CH2)n may be optionally substituted by one
C1-3alkyl group.

[0131]Reagents and Conditions: i) suitable solvent such as DCM, at a
lowered temperature e.g. from about 0° C. to room temperature.

[0132]Compounds of formula (XLI) are commercially available, for example,
from Aldrich and/or TCI Europe, and include 2-chloroethanesulfonyl
chloride and 3-chloropropanesulfonyl chloride.

[0134]According to a sixth process, F, a compound of formula (I) in which
R3 represents --N(R7)C(O)N(R8)--, and R3 represents
hydrogen, may be prepared by reacting a compound of formula (Va)

##STR00023##

with a compound of formula (IX)

R4--N═C═O (IX)

wherein R1, a, R4 and R7 are as defined hereinabove, n
represents 1 to 6 and (CH2)n may be optionally substituted by
one C1-3alkyl group.

[0135]The reaction may typically be carried out using a suitable solvent,
such as DCM. The reaction is usually carried out at ambient temperature
for an appropriate length of time such as overnight, for example.

[0136]Compounds of formula (Va) may be prepared according to Schemes 6 and
7 above, in which R5 is R7.

[0138]According to a seventh process, G, a compound of formula (I) in
which R3 represents --N(R7)C(O)N(R8)-- may be prepared by
reacting a compound of formula (X)

##STR00024##

with a compound of formula (XIa)

##STR00025##

wherein R1, a, R4, R7 and R3 are as defined
hereinabove, n represents 1 to 6 and (CH2)n may be optionally
substituted by one C1-3alkyl group.

[0139]The reaction may typically be carried out in a suitable solvent such
as THF or DCM, usually at an elevated temperature for example at reflux.

[0140]Compounds of formula (X) may be prepared according to Scheme 10
below.

[0141]Compounds of formula (XIa) are commercially available, for which see
compounds of formula (XI) in which R6 is R3 (see after Scheme
9, above).

##STR00026##

wherein R1, a and R7 are as defined hereinabove, n represents 1
to 6 and (CH2)n may be optionally substituted by one
C1-3alkyl group.

[0142]Reagents and Conditions: i) 1 equivalent 1,1'-carbonyldiimidazole,
in an appropriate solvent such as THF or DCM.

[0143]Compounds of formula (Va) may be prepared according to Schemes 6 and
7 above, in which R5 is R7.

[0144]The compound of formula (XLII), 1,1'-carbonyldiimidazole, is
commercially available, for example, from Aldrich.

[0145]According to an eighth process, H, a compound of formula (I), may be
prepared by interconversion from other compounds of formula (I).

[0146]Interconversions include, but are not limited to alkylation and
deprotection, under standard conditions well known to those skilled in
the art.

[0147]Thus, typically, an alkylation reaction may be carried out between a
compound of formula (I) and a C1-6alkyl, activated to substitution
by means of a leaving group such as halogen, such as chlorine or bromine,
or an activated hydroxyl group, such as mesylate or tosylate. The
reaction usually takes place in the presence of a suitable base such as
triethylamine, N,N'-diisopropylethylamine or sodium hydride, in an
appropriate solvent such as 2-butanone or DMF, optionally at an
appropriate elevated temperature such as at about 80° C.

[0148]According to a ninth process, I, a salt of a compound of formula (I)
may be prepared by exchange of counterions, or precipitation of said salt
from the free base.

[0149]Compounds of formula (I) may be further purified by methods
well-known to those skilled in the art, for example by recrystallisation,
column chromatography (which may be manual or automated, for example
mass-directed), preparative TLC and the like. A suitable solvent system
for recrystallisation of compounds of formula (I) in which R3
represents --N(R5)SO2-- and R4 represents C1-6alkyl
is methanol/ethyl acetate.

[0150]Examples of protecting groups that may be employed in the synthetic
routes described and the means for their removal can be found in T. W.
Greene et al. `Protective Groups in Organic Synthesis` (3rd edition, J.
Wiley and Sons, 1999). Suitable amine protecting groups include sulfonyl
(e.g. tosyl), acyl (e.g. acetyl, 2',2',2'-trichloroethoxycarbonyl,
benzyloxycarbonyl or t-butoxycarbonyl) and arylalkyl (e.g. benzyl), which
may be removed by hydrolysis (e.g. using an acid such as hydrogen
chloride in dioxane or trifluoroacetic acid in dichloromethane) or
reductively (e.g. hydrogenolysis of a benzyl group or reductive removal
of a 2',2',2'-trichloroethoxycarbonyl group using zinc in acetic acid) as
appropriate. Other suitable amine protecting groups include
trifluoroacetyl (--COCF3), which may be removed by base catalysed
hydrolysis or a solid phase resin bound benzyl group, such as a
Merrifield resin bound 2,6-dimethoxybenzyl group (Ellman linker), which
may be removed by acid cleavage, for example with trifluoroacetic acid.

[0151]It will be appreciated that novel intermediates described herein
form another embodiment of the present invention.

[0152]Examples of disease states in which a compound of formula (I), or a
pharmaceutically acceptable salt thereof potentially may have beneficial
anti-inflammatory and/or anti-allergic effects include inflammatory
and/or allergic diseases of the respiratory tract, such as allergic
rhinitis (seasonal and perennial) or other diseases such as bronchitis
(including chronic bronchitis), asthma (including allergen-induced
asthmatic reactions), chronic obstructive pulmonary disease (COPD) and
sinusitis.

[0153]Furthermore, the compounds of formula (I) may be of use in the
treatment of nephritis, skin diseases such as psoriasis, eczema, allergic
dermatitis and hypersensitivity reactions. Also, the compounds of formula
(I) may be useful in the treatment of insect bites and stings.

[0154]The compounds of formula (I) may also be of use in the treatment of
nasal polyposis, conjunctivitis (e.g allergic conjunctivitis) or
pruritis.

[0155]A disease of particular interest is allergic rhinitis.

[0156]Other diseases in which histamine may have a pathophysiological role
include non-allegic rhinitis, and also diseases of the gastrointestinal
tract such as intestinal inflammatory diseases including inflammatory
bowel disease (e.g. Crohn's disease or ulcerative colitis) and intestinal
inflammatory diseases secondary to radiation exposure or allergen
exposure.

[0157]It will be appreciated by those skilled in the art that references
herein to treatment or therapy may extend to prophylaxis as well as the
treatment of established conditions.

[0158]As mentioned above, compounds of formula (I) may be useful as
therapeutic agents. There is thus provided a compound of formula (I) or a
pharmaceutically acceptable salt thereof for use in therapy.

[0159]In another embodiment, there is provided a compound which is
6-butyl-8-({1-[3-(ethylsulfonyl)propyl]-4-piperidinyl}oxy)quinoline, or a
pharmaceutically acceptable salt thereof for use in therapy.

[0160]In another embodiment, there is provided a compound which is
N-(4-{4-[(6-butyl-8-quinolinyl)oxy]-1-piperidinyl}butyl)ethanesulfonamide-
, or a pharmaceutically acceptable salt (such as the dihydrochloride salt)
thereof for use in therapy.

[0161]In another embodiment, there is provided a compound of formula (I)
or a pharmaceutically acceptable salt thereof for use in the treatment of
any of the above diseases (e.g. allergic rhinitis).

[0162]In another embodiment, there is provided a compound which is
6-butyl-8-({1-[3-(ethylsulfonyl)propyl]-4-piperidinyl}oxy)quinoline, or a
pharmaceutically acceptable salt thereof for use in the treatment of any
of the above diseases (e.g. allergic rhinitis).

[0163]In another embodiment, there is provided a compound which is
N-(4-{4-[(6-butyl-8-quinolinyl)oxy]-1-piperidinyl}butyl)ethanesulfonamide-
, or a pharmaceutically acceptable salt (such as the dihydrochloride salt)
thereof for use in the treatment of any of the above diseases (e.g.
allergic rhinitis).

[0164]In another embodiment, there is provided the use of a compound of
formula (I) or a pharmaceutically acceptable salt thereof for the
manufacture of a medicament for the treatment of any of the above
diseases (e.g. allergic rhinitis).

[0165]In another embodiment, there is provided the use of a compound which
is 6-butyl-8-({1-[3-(ethylsulfonyl)propyl]-4-piperidinyl}oxy)quinoline,
or a pharmaceutically acceptable salt thereof for the manufacture of a
medicament for the treatment of any of the above diseases (e.g. allergic
rhinitis).

[0166]In another embodiment, there is provided the use of a compound which
is N-(4-{4-[(6-butyl-8-quinolinyl)oxy]-1-piperidinyl}butyl)ethanesulfonam-
ide, or a pharmaceutically acceptable salt (such as the dihydrochloride
salt) thereof for the manufacture of a medicament for the treatment of
any of the above diseases (e.g. allergic rhinitis).

[0167]In another embodiment, there is provided a method for the treatment
(or prophylaxis) of any of the above diseases (for example inflammatory
and/or allergic diseases of the respiratory tract, e.g. allergic
rhinitis), in a patient in need thereof, which method comprises
administering an effective amount of a compound of formula (I) or a
pharmaceutically acceptable salt thereof.

[0168]In another embodiment, there is provided a method for the treatment
(or prophylaxis) of any of the above diseases (for example inflammatory
and/or allergic diseases of the respiratory tract, e.g. allergic
rhinitis), in a patient in need thereof, which method comprises
administering an effective amount of a compound which is
6-butyl-8-({1-[3-(ethylsulfonyl)propyl]-4-piperidinyl}oxy)quinoline, or a
pharmaceutically acceptable salt thereof.

[0169]In another embodiment, there is provided a method for the treatment
(or prophylaxis) of any of the above diseases (for example inflammatory
and/or allergic diseases of the respiratory tract, e.g. allergic
rhinitis), in a patient in need thereof, which method comprises
administering an effective amount of a compound which is
N-(4-{4-[(6-butyl-8-quinolinyl)oxy]-1-piperidinyl}butyl)ethanesulfonamide-
, or a pharmaceutically acceptable salt (such as the dihydrochloride salt)
thereof.

[0170]When used in therapy, the compounds of formula (I) or
pharmaceutically acceptable salts thereof may typically be formulated in
a suitable pharmaceutical composition. Such pharmaceutical compositions
may be prepared using standard procedures.

[0171]Thus, there is provided a composition which comprises a compound of
formula (I) or a pharmaceutically acceptable salt thereof and one or more
(e.g. 10 or fewer) pharmaceutically acceptable carriers and/or
excipients.

[0172]In another embodiment, there is provided a composition which
comprises a compound which is
6-butyl-8-({1-[3-(ethylsulfonyl)propyl]-4-piperidinyl}oxy)quinoline, or a
pharmaceutically acceptable salt thereof and one or more pharmaceutically
acceptable carriers and/or excipients.

[0173]In another embodiment, there is provided a composition which
comprises a compound which is
N-(4-{4-[(6-butyl-8-quinolinyl)oxy]-1-piperidinyl}butyl)ethanesulfonamide-
, or a pharmaceutically acceptable salt (such as the dihydrochloride salt)
thereof and one or more pharmaceutically acceptable carriers and/or
excipients.

[0174]A composition comprising a compound of formula (I) or a
pharmaceutically acceptable salt thereof, which may be prepared by
admixture, suitably at ambient temperature and atmospheric pressure, may
be suitable for topical administration (which includes epicutaneous,
inhaled, intranasal or ocular administration), enteral administration
(which includes oral or rectal administration) or parenteral
administration (such as by injection or infusion). Of interest are
compositions comprising a compound of formula (I) or a pharmaceutically
acceptable salt thereof, suitable for topical administration,
particularly suitable for intranasal administration.

[0175]Generally, compositions may be in the form of solutions or
suspensions (aqueous or non-aqueous), tablets, capsules, oral liquid
preparations, powders, granules, lozenges, lotions, creams, ointments,
gels, foams, reconstitutable powders or suppositories as required by the
route of administration.

[0176]Generally, the compositions comprising a compound of formula (I) or
a pharmaceutically acceptable salt thereof may contain from about 0.001
to 99% (w/w), or about 0.1 to 99% (w/w), such as from about 0.1 to 60%
(w/w), or about 10 to 60% (w/w), or about 0.01% to 2% (w/w) (based on the
total weight of the composition), of the compound of formula (I) or the
pharmaceutically acceptable salt thereof, depending on the route of
administration. The dose of the compound used in the treatment of the
aforementioned diseases will vary in the usual way with the seriousness
of the diseases, the weight of the sufferer, and other similar factors.
However, as a general guide, suitable unit doses may be about 0.05 to
1000 mg, for example about 0.05 to 200 mg, for example about 0.05 to 2
mg, or about 0.05 to 1 mg and such unit doses may be administered more
than once a day, for example two or three times a day or as desired. Such
therapy may extend for a number of weeks or months.

[0177]The proportion of the compound of formula (I) or a pharmaceutically
acceptable salt thereof in a topical composition will depend on the
precise type of composition to be prepared and the particular route of
administration, but will generally be within the range of from about
0.001 to 10% (w/w), based on the total weight of the composition.
Generally, however for most types of preparations the proportion used
will be within the range of from about 0.005 to 1% (w/w), such as about
0.01 to 1% (w/w), or about 0.025 to 0.9% (w/w) (based on the total weight
of the composition). However, in powders for inhalation the proportion
used will generally be within the range of from about 0.1 to 5% (w/w),
based on the total weight of the composition.

[0179]For compositions suitable for intranasal or inhaled administration,
the compound of formula (I) or a pharmaceutically acceptable salt thereof
may typically be in a particle-size-reduced form, which may be prepared
by conventional techniques, for example, micronisation, milling and/or
microfluidisation. Generally, the size-reduced (e.g. micronised) compound
of formula (I) or a pharmaceutically acceptable salt thereof can be
defined by a D50 value of about 0.5 to 10 microns, for example of
about 1 to 10 microns, such as of about 2 to 4 microns (for example as
measured using laser diffraction).

[0180]In one embodiment, compositions comprising a compound of formula (I)
or a pharmaceutically acceptable salt thereof are suitable for intranasal
administration. Intranasal compositions comprising a compound of formula
(I) or a pharmaceutically acceptable salt thereof may permit the
compound(s) to be delivered to all areas of the nasal cavities (the
target tissue) and further, may permit the compound(s) to remain in
contact with the target tissue for longer periods of time. A suitable
dosing regime for intranasal compositions would be for the patient to
inhale slowly through the nose subsequent to the nasal cavity being
cleared. During inhalation the composition would be administered to one
nostril while the other is manually compressed. This procedure would then
be repeated for the other nostril. Typically, one or two administrations
per nostril would be administered by the above procedure up to two or
three times each day, ideally once daily. Of particular interest are
intranasal compositions suitable for once daily administration.

[0181]The intranasal compositions containing a compound of formula (I) or
a pharmaceutically acceptable salt thereof may be in the form of an
aqueous suspension and/or an aqueous solution. Partial suspensions and/or
partial solutions are encompassed within the scope of the present
invention. Compositions comprising one compound which is in solution and
another compound which is in suspension are also included within the
scope of the present invention.

[0182]Intranasal compositions may optionally contain one or more
suspending/thickening agents, one or more preservatives, one or more
wetting agents, one or more isotonicity adjusting agents and/or one or
more co-solvents as desired. Compositions suitable for intranasal
administration may optionally further contain other excipients, such as
antioxidants (for example sodium metabisulphite), taste-masking agents
(such as menthol) and sweetening agents (for example dextrose, glycerol,
saccharin and/or sorbitol).

[0183]The skilled person would readily appreciate that some excipients may
perform more than one function, depending on the nature and number of
excipients used in the composition and the particular properties of the
therapeutic compound(s) and other carriers and/or excipients contained
therein.

[0184]The suspending/thickening agent(s), if included, will typically be
present in the intranasal composition in an amount of between about 0.1
and 5% (w/w), such as between about 1.5% and 2.4% (w/w), particularly
about 2.4% (w/w) based on the total weight of the composition. Examples
of suspending agents include, but are not limited to Avicel®
(microcrystalline cellulose and carboxymethylcellulose sodium),
carboxymethylcellulose sodium, veegum, tragacanth, bentonite,
methylcellulose, xanthan gum, carbopol and polyethylene glycols. In one
embodiment, an intranasal composition containing a compound of formula
(I) or a pharmaceutically acceptable salt thereof comprises a
suspending/thickening agent which is microcrystalline cellulose and
carboxymethylcellulose sodium. Suspending agents may also be included in
compositions suitable for inhaled, ocular and oral administration as
appropriate.

[0185]For stability purposes, intranasal compositions comprising a
compound of formula (I) or a pharmaceutically acceptable salt thereof may
be protected from microbial or fungal contamination and growth by
inclusion of a preservative. Examples of pharmaceutically acceptable
anti-microbial agents or preservatives include, but are not limited to
quaternary ammonium compounds (e.g. benzethonium chloride, cetrimide,
cetylpyridinium chloride, myristal picolinium chloride and lauralkonium
chloride. Another anti-microbial agent is benzalkonium chloride),
mercurial agents (e.g. phenylmercuric nitrate, phenylmercuric acetate and
thimerosal), alcoholic agents (e.g. chlorobutanol, phenylethyl alcohol
and benzyl alcohol), antibacterial esters (e.g. esters of
para-hydroxybenzoic acid), chelating agents such as disodium
ethylenediaminetetraacetate (EDTA) and other anti-microbial agents such
as chlorhexidine, chlorocresol, sorbic acid and its salts (such as
potassium sorbate) and polymyxin. Examples of pharmaceutically acceptable
anti-fungal agents or preservatives may include, but are not limited to,
sodium benzoate, sorbic acid, sodium propionate, methyl paraben, ethyl
paraben, propyl paraben and butyl paraben. The preservative, if included,
may be present in an amount of between about 0.001 and 1% (w/w), such as
about 0.015% (w/w), and for example between about 0.015% to 0.5% (w/w) or
between about 0.015 to 0.3% (w/w), based on the total weight of the
composition. In one embodiment, an intranasal composition containing a
compound of formula (I) or a pharmaceutically acceptable salt thereof
comprises a preservative which is selected from EDTA and/or potassium
sorbate. Preservatives may be included in compositions suitable for other
routes of administration as appropriate.

[0186]Compositions which contain a suspended medicament may include a
pharmaceutically acceptable wetting agent which functions to wet the
particles of medicament to facilitate dispersion thereof in the aqueous
phase of the composition. Typically, the amount of wetting agent used
will not cause foaming of the dispersion during mixing. Examples of
wetting agents include, but are not limited to fatty alcohols, esters and
ethers, such as polyoxyethylene (20) sorbitan monooleate (Polysorbate
80), macrogol ethers and poloxamers. The wetting agent may be present in
intranasal compositions in an amount of between about 0.005 to 0.05%
(w/w), such as between about 0.001 and 0.05% (w/w), for example about
0.025% (w/w), based on the total weight of the composition. In one
embodiment, an intranasal composition containing a compound of formula
(I) or a pharmaceutically acceptable salt thereof comprises a wetting
agent which is polyoxyethylene (20) sorbitan monooleate (Polysorbate 80).
Wetting agents may be included in compositions suitable for other routes
of administration, e.g. for inhaled and/or ocular administration, as
appropriate.

[0187]An isotonicity adjusting agent may be included to achieve
isotonicity with body fluids e.g. fluids of the nasal cavity, resulting
in reduced levels of irritancy. Examples of isotonicity adjusting agents
include, but are not limited to sodium chloride, dextrose, xylitol and
calcium chloride. An isotonicity adjusting agent may be included in
intranasal compositions in an amount of between about 0.1 and 10% (w/w),
for example between about 4.5 to 5.5% (w/w), such as about 5.0% (w/w), or
between about 0.5 to 1% (w/w), or about 0.75% (w/w), based on the total
weight of the composition. In one embodiment, an intranasal composition
containing a compound of formula (I) or a pharmaceutically acceptable
salt thereof comprises an isotonicity adjusting agent which is xylitol.
In another embodiment, the intranasal composition does not contain an
isotonicity adjusting agent. Isotonicity adjusting agents may also be
included in compositions suitable for other routes of administration, for
example in compositions suitable for inhaled, ocular, oral liquid and
parenteral administration, as appropriate.

[0188]One or more co-solvent(s) may be included to aid solubility of the
active compound(s) and/or other excipients. Examples of pharmaceutically
acceptable co-solvents include, but are not limited to, propylene glycol,
dipropylene glycol, ethylene glycol, glycerol, ethanol, polyethylene
glycols (for example PEG300 or PEG400) and methanol. The co-solvent(s),
if present, may be included in an amount of from about 0.05 to 20% (w/w),
such as from about 1.5 to 17.5% (w/w), or from about 1.5 to 7.5% (w/w),
or from about 0.05% to 0.5% (w/w) based on the total weight of the
composition. In one embodiment, an intranasal composition containing a
compound of formula (I) or a pharmaceutically acceptable salt thereof
comprises a co-solvent which is propylene glycol. Co-solvents may also be
included in compositions suitable for other routes of administration, as
appropriate.

[0189]Further, the intranasal compositions comprising a compound of
formula (I) or a pharmaceutically acceptable salt thereof may be buffered
by the addition of suitable buffering agents such as sodium citrate,
citric acid, trometarol, phosphates such as disodium phosphate (for
example the dodecahydrate, heptahydrate, dihydrate and anhydrous forms)
or sodium phosphate and mixtures thereof. In one embodiment, an
intranasal composition containing a compound of formula (I) or a
pharmaceutically acceptable salt thereof comprises buffering agents which
are sodium citrate and/or citric acid. Buffering agents may also be
included in compositions suitable for other routes of administration as
appropriate.

[0190]In one embodiment, there is provided an intranasal aqueous
compositon containing a compound of formula (I) or a pharmaceutically
acceptable salt thereof and further comprising [0191]a) a
suspending/thickening agent; [0192]b) a preservative; [0193]c) a wetting
agent; [0194]d) a co-solvent; and optionally [0195]e) an isotonicity
adjusting agent.

[0196]Compositions for administration topically to the nose (for example,
for the treatment of rhinitis) or to the lung, include pressurised
aerosol compositions and aqueous compositions delivered to the nasal
cavities by pressurised pump. Compositions which are non-pressurised and
are suitable for administration topically to the nasal cavity are of
particular interest. Suitable compositions contain water as the diluent
or carrier for this purpose. Aqueous compositions for administration to
the lung or nose may be provided with conventional excipients such as
buffering agents, tonicity modifying agents and the like. Aqueous
compositions may also be administered to the nose by nebulisation.

[0197]A fluid dispenser may typically be used to deliver a fluid
composition to the nasal cavities. The fluid composition may be aqueous
or non-aqueous, but typically aqueous. Such a fluid dispenser may have a
dispensing nozzle or dispensing orifice through which a metered dose of
the fluid composition is dispensed upon the application of a user-applied
force to a pump mechanism of the fluid dispenser. Such fluid dispensers
are generally provided with a reservoir of multiple metered doses of the
fluid composition, the doses being dispensable upon sequential pump
actuations. The dispensing nozzle or orifice may be configured for
insertion into the nostrils of the user for spray dispensing of the fluid
composition into the nasal cavity. A fluid dispenser of the
aforementioned type is described and illustrated in WO05/044354 the
entire content of which is hereby incorporated herein by reference. The
dispenser has a housing which houses a fluid discharge device having a
compression pump mounted on a container for containing a fluid
composition. The housing has at least one finger-operable side lever
which is movable inwardly with respect to the housing to cam the
container upwardly in the housing to cause the pump to compress and pump
a metered dose of the composition out of a pump stem through a nasal
nozzle of the housing. In one embodiment, the fluid dispenser is of the
general type illustrated in FIGS. 30-40 of WO05/044354.

[0198]Aqueous compositions containing a compound of formula (I) or a
pharmaceutically acceptable salt thereof may also be delivered by a pump
as disclosed in WO2007/138084, for example as disclosed with reference to
FIGS. 22-46 thereof, or as disclosed in GB0723418.0, for example as
disclosed with reference to FIGS. 7-32 thereof, both of which prior
patent applications are incorporated herein by reference in their
entirety. The pump may be actuated by an actuator as disclosed in FIGS.
1-6 of said GB0723418.0.

[0199]In one embodiment, there is provided an intranasal composition
comprising a compound of formula (I) or a pharmaceutically acceptable
salt thereof. In another embodiment, such an intranasal composition is
benzalkonium chloride-free.

[0200]In another embodiment, there is provided an intranasal composition
comprising a compound which is
N-(4-{4-[(6-butyl-8-quinolinyl)oxy]-1-piperidinyl}butyl)ethanesulfonamide-
, or a pharmaceutically acceptable salt (such as a dihydrochloride salt)
thereof. In another embodiment, such an intranasal composition is
benzalkonium chloride-free.

[0201]Inhaled administration involves topical administration to the lung,
such as by aerosol or dry powder composition.

[0202]Aerosol compositions suitable for inhaled administration may
comprise a solution or fine suspension of the compound in a
pharmaceutically acceptable aqueous or non-aqueous solvent. Aerosol
compositions suitable for inhalation can be either a suspension or a
solution and generally contain a compound of formula (I) or a
pharmaceutically acceptable salt thereof and a suitable propellant such
as a fluorocarbon or hydrogen-containing chlorofluorocarbon or mixtures
thereof, such as hydrofluoroalkanes, e.g. 1,1,1,2-tetrafluoroethane,
1,1,1,2,3,3,3-heptafluoro-n-propane or a mixture thereof. The aerosol
composition may optionally contain additional excipients well known in
the art such as surfactants or co-solvents. Examples of surfactants
include, but are not limited to oleic acid, lecithin, an oligolactic acid
or derivative e.g. as described in WO94/21229 and WO98/34596. An example
of a co-solvent includes, but is not limited to ethanol. Aerosol
compositions may be presented in single or multidose quantities in
sterile form in a sealed container, which may take the form of a
cartridge or refill for use with an atomising device or inhaler.
Alternatively, the sealed container may be a unitary dispensing device
such as a single dose nasal inhaler or an aerosol dispenser fitted with a
metering valve (metered dose inhaler), which is intended for disposal
once the contents of the container have been exhausted.

[0203]Dry powder inhalable compositions may take the form of capsules and
cartridges of, for example, gelatine, or blisters of, for example,
laminated aluminium foil, for use in an inhaler or insufflator. Such
compositions may be formulated comprising a powder mix of a compound of
formula (I) or a pharmaceutically acceptable salt thereof and a suitable
powder base such as lactose or starch.

[0204]Optionally, for dry powder inhalable compositions, a composition
suitable for inhaled administration may be incorporated into a plurality
of sealed dose containers (e.g. comprising the dry powder composition)
mounted longitudinally in a strip or ribbon inside a suitable inhalation
device. The container is rupturable or peel-openable on demand and the
dose of e.g. the dry powder composition may be administered by inhalation
via the device such as the DISKUS® device, marketed by
GlaxoSmithKline. The DISKUS® inhalation device is for example
described in GB 2242134 A, and in such a device, at least one container
for the composition in powder form (the container or containers may, for
example, be a plurality of sealed dose containers mounted longitudinally
in a strip or ribbon) is defined between two members peelably secured to
one another; the device comprises: a means of defining an opening station
for the said container or containers; a means for peeling the members
apart at the opening station to open the container; and an outlet,
communicating with the opened container, through which a user can inhale
the composition in powder form from the opened container.

[0205]Aerosol compositions are typically arranged so that each metered
dose or "puff" of aerosol contains about 20 μg-2000 μg,
particularly about 20 μg-500 μg of a compound of formula (I) or a
pharmaceutically acceptable salt thereof. Administration may be once
daily or several times daily, for example 2, 3, 4 or 8 times, giving for
example 1, 2 or 3 doses each time. The overall daily dose with an aerosol
will be within the range of about 100 μg-10 mg, such as between about
200 μg-2000 μg. The overall daily dose and the metered dose
delivered by capsules and cartridges in an inhaler or insufflator will
generally be double those with aerosol compositions.

[0206]In another embodiment, there is provided a composition comprising a
compound of formula (I) or a pharmaceutically acceptable salt thereof
which is suitable for epicutaneous administration. An epicutaneous
composition to be applied to the affected area e.g. the skin, by one or
more application per day, may be in the form of, for example, an
ointment, a cream, an emulsion, a lotion, a foam, a spray, an aqueous
gel, or a microemulsion. Such compositions may optionally contain one or
more solubilising agents, skin-penetration-enhancing agents, surfactants,
fragrances, preservatives or emulsifying agents.

[0207]Ointments, creams and gels, may, for example, be formulated with an
aqueous or oily base with the addition of suitable thickening and/or
gelling agent and/or solvents. Such bases may thus, for example, include
water and/or an oil such as liquid paraffin or a vegetable oil such as
arachis oil or castor oil, or a solvent such as polyethylene glycol.
Thickening agents and gelling agents which may be used according to the
nature of the base include soft paraffin, aluminium stearate, cetostearyl
alcohol, polyethylene glycols, woolfat, beeswax, carboxypolymethylene and
cellulose derivatives, and/or glyceryl monostearate and/or non-ionic
emulsifying agents. Lotions may be formulated with an aqueous or oily
base and will in general also contain one or more emulsifying agents,
stabilising agents, dispersing agents, suspending agents or thickening
agents.

[0208]In another embodiment, there is provided a composition comprising a
compound of formula (I) or a pharmaceutically acceptable salt thereof
which is suitable for ocular administration. Such compositions may
optionally contain one or more suspending agents, one or more
preservatives, one or more wetting/lubricating agents and/or one or more
isotonicity adjusting agents. Examples of ophthalmic wetting/lubricating
agents may include cellulose derivatives, dextran 70, gelatin, liquid
polyols, polyvinyl alcohol and povidone such as cellulose derivatives and
polyols.

[0209]In another embodiment, there is provided a composition comprising a
compound which is
N-(4-{4-[(6-butyl-8-quinolinyl)oxy]-1-piperidinyl}butyl)ethanesulfonamide-
, or a pharmaceutically acceptable salt (such as a dihydrochloride salt)
thereof which is suitable for ocular administration.

[0210]In another embodiment, there is provided a composition comprising a
compound of formula (I) or a pharmaceutically acceptable salt thereof
which is suitable for oral administration. Tablets and capsules for oral
administration may be in unit dose form, and may contain conventional
excipients, such as binding agents, fillers, tabletting lubricants,
disintegrants and acceptable wetting agents. The tablets may be coated
according to methods well known in normal pharmaceutical practice.

[0211]Oral liquid preparations may be in the form of, for example, aqueous
or oily suspension, solutions, emulsions, syrups or elixirs, or may be in
the form of a dry product for reconstitution with water or other suitable
vehicle before use. Such liquid preparations may contain conventional
additives such as suspending agents, emulsifying agents, non-aqueous
vehicles (which may include edible oils), preservatives, and, if desired,
conventional flavourings or colorants.

[0212]In another embodiment, there is provided a composition comprising a
compound of formula (I) or a pharmaceutically acceptable salt thereof
which is suitable for parenteral administration. Fluid unit dosage forms
suitable for parenteral administration may be prepared utilising a
compound of formula (I) or pharmaceutically acceptable salt thereof and a
sterile vehicle which may be aqueous or oil based. The compound,
depending on the vehicle and concentration used, may be either suspended
or dissolved in the vehicle. In preparing solutions, the compound may be
dissolved for injection and filter sterilised before filling into a
suitable vial or ampoule and sealing. Optionally, adjuvants such as a
local anaesthetic, preservatives and buffering agents may be dissolved in
the vehicle. To enhance the stability, the composition may be frozen
after filling into the vial and the water removed under vacuum. The
lyophilised parenteral composition may be reconstituted with a suitable
solvent just prior to administration. Parenteral suspensions may be
prepared in substantially the same manner, except that the compound is
suspended in the vehicle instead of being dissolved, and sterilisation
cannot be accomplished by filtration. The compound may be sterilised by
exposure to ethylene oxide before suspension in a sterile vehicle. A
surfactant or wetting agent may be included in the composition to
facilitate uniform distribution of the compound.

[0214]It will be clear to a person skilled in the art that, where
appropriate, the other therapeutic agent(s) may be used in the form of
salts, (e.g. as alkali metal or amine salts or as acid addition salts),
or prodrugs, or as esters (e.g. lower alkyl esters), or as solvates (e.g.
hydrates) to optimise the activity and/or stability and/or physical
characteristics (e.g. solubility) of the therapeutic agent. It will be
clear also that where appropriate, the therapeutic agents may be used in
optically pure form.

[0215]There is provided, in another embodiment, a combination comprising a
compound of formula (I) or a pharmaceutically acceptable salt thereof
together with one or more (such as one or two, e.g. one) other
therapeutically active agents, optionally with one or more
pharmaceutically acceptable carriers and/or excipients.

[0216]In another embodiment, there is provided a combination comprising a
compound which is
6-butyl-8-({1-[3-(ethylsulfonyl)propyl]-4-piperidinyl}oxy)quinoline, or a
pharmaceutically acceptable salt thereof, together with one or more (such
as one or two, e.g. one) other therapeutically active agents (such as
those described herein), optionally with one or more pharmaceutically
acceptable carriers and/or excipients.

[0217]In another embodiment, there is provided a combination comprising a
compound which is
N-(4-{4-[(6-butyl-8-quinolinyl)oxy]-1-piperidinyl}butyl)ethanesulfonamide-
, or a pharmaceutically acceptable salt (such as a dihydrochloride salt)
thereof together with one or more (such as one or two, e.g. one) other
therapeutically active agents (such as those described herein),
optionally with one or more pharmaceutically acceptable carriers and/or
excipients.

[0218]In another embodiment, there is provided a combination comprising a
compound of formula (I) or a pharmaceutically acceptable salt thereof and
an H3 and/or H4 antagonist.

[0219]Other histamine receptor antagonists which may be used alone, or in
combination with an H1 receptor antagonist include antagonists (and/or
inverse agonists) of the H4 receptor, for example, the compounds
disclosed in Jablonowski et al., J. Med. Chem. 46:3957-3960 (2003), and
antagonists (and/or inverse agonists) of the H3 receptor, for example the
compounds described in WO2004/035556, the compounds described in
WO2006/125665 and the compounds described in WO2006/090142.

[0220]In another embodiment, there is provided a combination comprising a
compound of formula (I) or a pharmaceutically acceptable salt thereof and
a β2-adrenoreceptor agonist.

[0221]Examples of β2-adrenoreceptor agonists include salmeterol
(which may be a racemate or a single enantiomer, such as the
R-enantiomer), salbutamol (which may be a racemate or a single enantiomer
such as the R-enantiomer), formoterol (which may be a racemate or a
single diastereomer such as the R,R-diastereomer), salmefamol, fenoterol,
carmoterol, etanterol, naminterol, clenbuterol, pirbuterol, flerbuterol,
reproterol, bambuterol, indacaterol, terbutaline and salts thereof, for
example the xinafoate (1-hydroxy-2-naphthalenecarboxylate) salt of
salmeterol, the sulfate salt or free base of salbutamol or the fumarate
salt of formoterol. In one embodiment, combinations containing a compound
of formula (I) may include longer-acting β2-adrenoreceptor
agonists, for example, compounds which provide effective bronchodilation
for about 12 h or longer.

[0234]There is provided, in a further embodiment, a combination comprising
a compound of formula (I) or a pharmaceutically acceptable salt thereof,
together with a corticosteroid, such as fluticasone propionate or
6α,9α-difluoro-17α-[(2-furanylcarbonyl)oxy]-11β-hy-
droxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioic acid
S-fluoromethyl ester (fluticasone furoate) or mometasone furoate. Such
combinations may be of particular interest for intranasal administration.

[0235]In another embodiment, there is provided a combination comprising a
compound which is
N-(4-{4-[(6-butyl-8-quinolinyl)oxy]-1-piperidinyl}butyl)ethanesulfonamide-
, or a pharmaceutically acceptable salt (such as a dihydrochloride salt)
thereof together with
6α,9α-difluoro-17α-[(2-furanylcarbonyl)oxy]-11β-hy-
droxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioic acid
S-fluoromethyl ester (fluticasone furoate). In another embodiment, the
combination is suitable for intranasal administration.

[0236]In another embodiment, there is provided a combination comprising a
compound of formula (I) or a pharmaceutically acceptable salt thereof and
a glucocorticoid agonist.

[0237]Non-steroidal compounds having glucocorticoid agonism that may
possess selectivity for transrepression over transactivation and that may
be useful in combination therapy include those covered in the following
patent application and patents: WO03/082827, WO98/54159, WO04/005229,
WO04/009017, WO04/018429, WO03/104195, WO03/082787, WO03/082280,
WO03/059899, WO03/101932, WO02/02565, WO01/16128, WO0/66590, WO03/086294,
WO04/026248, WO03/061651, WO03/08277, WO06/000401, WO06/000398 and
WO06/015870.

[0240]In another embodiment there is provided the use of the compounds of
formula (I) or a pharmaceutically acceptable salt thereof in combination
with a phosphodiesterase 4 (PDE4) inhibitor. The PDE4-specific inhibitor
useful in this embodiment may be any compound that is known to inhibit
the PDE4 enzyme or which is discovered to act as a PDE4 inhibitor, and
which are selective PDE4 inhibitors, not compounds which inhibit other
members of the PDE family, such as PDE3 and PDE5, as well as PDE4.

[0241]Compounds which may be of interest include
cis-4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-carboxylic
acid, 2-carbomethoxy-4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphe-
nyl)cyclohexan-1-one and
cis-[4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-
-ol]. Also,
cis-4-cyano-4-[3-(cyclopentyloxy)-4-methoxyphenyl]cyclohexane-1-carboxyli-
c acid (also known as cilomilast) and its salts, esters, pro-drugs or
physical forms, which is described in U.S. Pat. No. 5,552,438 issued 3
Sep., 1996.

[0243]Further PDE4 inhibitors which may be of interest are disclosed in
the published international patent applications WO04/024728 (Glaxo Group
Ltd), WO04/056823 (Glaxo Group Ltd) and WO04/103998 (Glaxo Group Ltd). A
particular compound of interest is 6-({3-[(di
methylamino)carbonyl]phenyl}sulfonyl)-8-methyl-4-{[3-(methyloxy)phenyl]am-
ino}-3-quinolinecarboxamide or a pharmaceutically acceptable salt thereof,
which is described in International Patent Application WO04/103998.

[0244]In another embodiment, there is provided a combination comprising a
compound which is
N-(4-{4-[(6-butyl-8-quinolinyl)oxy]-1-piperidinyl}butyl)ethanesulfonamide-
, or a pharmaceutically acceptable salt (such as a dihydrochloride salt)
thereof together with
6-({3-[(dimethylamino)carbonyl]phenyl}sulfonyl)-8-methyl-4-{[3-(methyloxy-
)phenyl]amino}-3-quinolinecarboxamide or a pharmaceutically acceptable
salt thereof.

[0245]In another embodiment, there is provided a combination comprising a
compound of formula (I) or a pharmaceutically acceptable salt thereof and
an anticholinergic agent.

[0246]Anticholinergic agents are those compounds that act as antagonists
at the muscarinic receptors, in particular those compounds which are
antagonists of the M1 or M3 receptors, dual antagonists of the
M1/M3 or M2/M3, receptors or pan-antagonists of the
M1/M2/M3 receptors. Exemplary compounds for administration
via inhalation include ipratropium (for example, as the bromide, CAS
22254-24-6, sold under the name Atrovent), oxitropium (for example, as
the bromide, CAS 30286-75-0) and tiotropium (for example, as the bromide,
CAS 136310-93-5, sold under the name Spiriva). Also of interest are
revatropate (for example, as the hydrobromide, CAS 262586-79-8) and
LAS-34273 which is disclosed in WO01/04118. Exemplary compounds for oral
administration include pirenzepine (for example, CAS 28797-61-7),
darifenacin (for example, CAS 133099-04-4, or CAS 133099-07-7 for the
hydrobromide sold under the name Enablex), oxybutynin (for example, CAS
5633-20-5, sold under the name Ditropan), terodiline (for example, CAS
15793-40-5), tolterodine (for example, CAS 124937-51-5, or CAS
124937-52-6 for the tartrate, sold under the name Detrol), otilonium (for
example, as the bromide, CAS 26095-59-0, sold under the name Spasmomen),
trospium chloride (for example, CAS 10405-02-4) and solifenacin (for
example, CAS 242478-37-1, or CAS 242478-38-2, or the succinate also known
as YM-905 and sold under the name Vesicare).

[0247]Other anticholinergic agents include compounds which are disclosed
in U.S. patent application 60/487,981, published as WO2005/009439 and
those compounds disclosed in U.S. patent application 60/511,009,
published as WO2005/037280.

[0248]The combinations referred to above may conveniently be presented for
use in the form of a pharmaceutical composition and thus the present
invention further provides pharmaceutical compositions comprising a
combination as defined above optionally together with a pharmaceutically
acceptable carrier and/or excipient.

[0249]The individual compounds of such combinations may be administered
either sequentially in separate pharmaceutical compositions or
simultaneously in combined pharmaceutical compositions. Appropriate doses
of known therapeutic agents will be readily appreciated by those skilled
in the art.

[0250]Compounds of formula (I) may be prepared by the methods described
below or by similar methods. Thus the following Intermediates and
Examples illustrate the preparation of the compounds of formula (I), and
are not to be considered as limiting the scope of the disclosure in any
way.

[0258]The Flashmaster II is an automated multi-user flash chromatography
system, available from Argonaut Technologies Ltd, which utilises
disposable, normal phase, SPE cartridges (2 g to 100 g). It provides
quaternary on-line solvent mixing to enable gradient methods to be run.
Samples are queued using the multi-functional open access software, which
manages solvents, flow-rates, gradient profile and collection conditions.
The system is equipped with a Knauer variable wavelength UV-detector and
two Gilson FC204 fraction-collectors enabling automated peak cutting,
collection and tracking.

[0259]Mass directed autopreparative (MDAP) HPLC was conducted on a Waters
FractionLynx system comprising of a Waters 600 pump with extended pump
heads, Waters 2700 autosampler, Waters 996 diode array and Gilson 202
fraction collector on a 10 cm×2.54 cm internal diameter ABZ+
column, eluting with 0.1% formic acid in water (solvent A) and 0.1%
formic acid in MeCN (solvent B), using an appropriate elution gradient
over 15 min at a flow rate of 20 mlmin-1 and detecting at 200-320 nm
at room temperature. Mass spectra were recorded on Micromass ZMD mass
spectrometer using electro spray positive and negative mode, alternate
scans. The software used was MassLynx 3.5 with OpenLynx and FractionLynx
options.

[0260]The 1H NMR spectra were recorded on a Bruker AV400 operating at
400 MHz. Standard deuterated solvents were used. Tetramethylsilane may
have been used as internal standard.

[0261]Reactions are routinely monitored by methods well known to those
skilled in the art, such as TLC, LCMS and/or HPLC. Such methods are used
to assess whether a reaction has gone to completion, and reaction times
may be varied accordingly.

[0262]The XRPD method which was employed to analyse crystalline forms of
compounds was as follows:

[0266]A solution of concentrated sulphuric acid (63 ml, 820 mmol) in water
(49.4 ml) was treated with sodium 3-nitro-benzenesulfonate (commercially
available, for example, from Aldrich) (47.9 g, 213 mmol) and glycerol
(commercially available, for example, from Fluka and/or Aldrich) (52 ml,
720 mmol) to give a thick grey suspension. This was heated to 110°
C. (internal temperature was 85° C.). 4-Bromo-2-fluoroaniline
(commercially available, for example, from Fluorochem and/or Aldrich) (38
g, 200 mmol) was added over 10 min in portions, during which the internal
temperature rose to 95° C. The reaction was heated to 140°
C. (internal temperature was 133° C.) and stirred overnight. The
reaction mixture was cooled and then poured into water (1000 ml) and
basified to pH 7 with aqueous ammonia (0.88 s.g, approximately 190 ml).
The brown precipitate that formed was collected by filtration and
partially dried. This solid (63 g) was loaded onto a column of silica
(1500 ml) and eluted with EtOAc to give the title compound as a light
brown solid (43.8 g, 97%). LCMS RT=2.87 min, ES+ve m/z 226/228
[M+H].sup.+.

Intermediate 2

6-Butyl-8-fluoroquinoline

##STR00028##

[0268]A mixture of 6-bromo-8-fluoroquinoline (for example, as prepared for
Intermediate 1) (24 g, 106 mmol) in DMF (150 ml) was treated under
nitrogen with potassium carbonate (33 g, 240 mmol), tributylborane
solution in THF (commercially available, for example, from Aldrich) (1M,
200 ml) and [1,1'-bis(diphenylphosphino) ferrocene palladium
(II)]chloride (1 g, 1.2 mmol). The resulting mixture was stirred under
nitrogen and heated at 75° C. overnight. The mixture was allowed
to cool, diluted with water and extracted with EtOAc (×3). The
combined organic layers were filtered through a frit to remove any
insoluble material and the filtrate washed with water. The organic layer
was dried (MgSO4), and the filtrate evaporated to dryness. The
residue was purified twice by flash chromatography eluting with DCM-EtOAc
(1:0 to 2:1) to afford the title compound (14.47 g, 67%). LCMS RT=3.38
min, ES+ve m/z 204 [M+H].sup.+.

[0270]A solution of 6-butyl-8-fluoroquinoline (for example, as prepared
for Intermediate 2) (14.4 g, 70.9 mmol) in NMP (20 ml) was added to a
mixture of tert-butyl-4-hydroxy-1-piperidinecarboxylate (commercially
available, for example, from Aldrich) (21.6 g, 108 mmol) and sodium
tert-butoxide (10.4 g, 108 mmol) in NMP (75 ml), and the resulting
mixture was stirred at 140° C. for approximately 90 min and then
allowed to cool overnight. The reaction mixture was treated with ammonium
chloride solution and extracted with EtOAc (×2). The combined
organic extracts were washed with water, dried (MgSO4), filtered and
evaporated to dryness. The residue was purified by flash chromatography
eluting with DCM-EtOAc (1:0 to 1:1) and then twice by Flashmaster
chromatography eluting with DCM-EtOAc (1:0 to 3:1) over 40 min to give
the title compound (22 g). LCMS RT=3.49 min, ES+ve m/z 385 [M+H].sup.+

Intermediate 4

6-Butyl-8-(4-piperidinyloxy)quinoline

##STR00030##

[0272]1,1-Dimethylethyl
4-[(6-butyl-8-quinolinyl)oxy]-1-piperidinecarboxylate (for example, as
prepared for Intermediate 3) (21.5 g, 56 mmol) was dissolved in DCM (50
ml) and trifluoroacetic acid (50 ml) was added very slowly. The mixture
was stirred at room temperature for 1 h. The solvent was evaporated to
dryness and the residue treated with saturated aqueous sodium carbonate
solution. The mixture was extracted with EtOAc (×2), washed with
water, and dried (MgSO4). The drying agent was removed by filtration
and the filtrate was evaporated to dryness (22 g). This was still a
trifluoracetic acid salt and was re-dissolved in EtOAc, washed with
aqueous sodium carbonate, water, and dried (MgSO4). The drying agent
was removed by filtration and the filtrate was evaporated to dryness to
afford the title compound (15.9 g). LCMS RT=2.45 min, ES+ve m/z 285
[M+H].sup.+.

Intermediate 5

6-Chloro-8-fluoroquinoline

[0273]A solution of concentrated sulphuric acid (16 ml, 300 mmol) in water
(12 ml) was treated with sodium 3-nitro-benzenesulfonate (commercially
available, for example, from Aldrich) (11.3 g, 50 mmol) and glycerol
(commercially available, for example, from Fisher and/or Aldrich) (12 ml,
160 mmol) to give a suspension. This was heated to 110° C. with
stirring, and 4-chloro-2-fluoroaniline (commercially available, for
example, from Aldrich) (5.6 ml, 50 mmol) was added. The reaction was
heated to 140° C. and stirred overnight. The reaction mixture was
cooled and then poured into water (400 ml) and basified to pH 11 with
aqueous ammonium hydroxide (0.88 s.g., 60 ml). The brown precipitate that
formed was collected by filtration and dried under suction. EtOAc was
then added to the sinter funnel, dissolving most of the material to give
a brown solution. This filtrate was concentrated in vacuo to give a brown
solid (7.7 g). This was purified by chromatography on silica (2×100
g, eluting with 0-50% EtOAc-cyclohexane over 60 min). The relevant
fractions were concentrated in vacuo to give the title compound as a
yellow solid (6.5 g, 70%) LCMS RT=2.78 min, ES+ve m/z 182/184
[M+H].sup.+.

[0274]6-Chloro-8-fluoroquinoline (for example, as prepared for
Intermediate 5) (2.18 g, 12 mmol) was dissolved in NMP (20 ml) and
treated with 1,1-dimethylethyl 4-hydroxy-1-piperidinecarboxylate
(commercially available, for example, from Acros and/or Aldrich) (4.85 g,
24 mmol) and sodium tert-butoxide (2.38 g, 25 mmol). Further NMP was
added (5 ml) and the resulting mixture was stirred at 140° C. for
1 h, and then allowed to cool overnight. The reaction mixture was treated
with water and extracted with toluene. The organic extract was washed
with water (×3), dried (MgSO4), and concentrated in vacuo. The
residue was purified by silica chromatography (2×70 g), eluting
with 0-100% EtOAc-cyclohexane over 30 min. The relevant fractions were
concentrated in vacuo to give the title compound as a yellow gum (2.73 g,
63%): LCMS RT=3.37 min, ES+ve m/z 363/365 [M+H].sup.+.

[0275]1,1-Dimethylethyl
4-[(6-chloro-8-quinolinyl)oxy]-1-piperidinecarboxylate (for example, as
prepared for Intermediate 6) (2.73 g, 7.5 mmol) was dissolved in a
mixture of THF (55 ml), NMP (5.6 ml) and iron (III) acetylacetonate (220
mg, 0.62 mmol) were added, and the mixture was cooled to 0° C. and
stirred under a nitrogen atmosphere. n-Pentyl magnesium bromide
(commercially available, for example, from TCI-Europe and/or Aldrich) was
added dropwise over 9 min. The stirring was continued at 0° C. for
1 h, and the reaction was then allowed to warm to room temperature with
stirring overnight. The reaction mixture was treated with aqueous
ammonium chloride solution and extracted with EtOAc (×3). The
combined organic extracts were filtered, dried (MgSO4), and
concentrated in vacuo. The residue was purified by silica chromatography
(2×100 g), eluting with 0-50% EtOAc-cyclohexane over 40 min. The
relevant fractions were concentrated in vacuo to give the title compound
as a yellow oil (2.2 g, 74%): LCMS RT=3.76 min, ES+ve m/z 399
[M+H].sup.+.

Intermediate 8

6-Pentyl-8-(4-piperidinyloxy)quinoline

[0276]1,1-Dimethylethyl
4-[(6-pentyl-8-quinolinyl)oxy]-1-piperidinecarboxylate (for example, as
prepared for Intermediate 7) (2.20 g, 5.52 mmol) was dissolved in dioxane
(10 ml) and the solution was treated with a solution of hydrogen chloride
in dioxane (4M, 12.5 ml). The mixture was stirred under nitrogen
overnight at room temperature, and then concentrated in vacuo. The
residue was applied to a SCX-2 ion exchange cartridge (70 g) which had
been preconditioned with methanol. The cartridge was washed with
methanol, and then eluted with 10% aqueous 0.88 s.g. ammonia in methanol.
The relevant basic fractions were concentrated in vacuo to give the title
compound (1.88 g); LCMS RT=2.70 min, ES+ve m/z 299 [M+H].sup.+.

[0282]Sodium ethanethiolate (commercially available, for example, from
Aldrich) (2.0 g, 24 mmol) in ethanol (24 ml) was treated with
1-bromo-3-chloropropane (commercially available, for example, from
Aldrich) (2.35 ml, 24 mmol) and the mixture was stirred at room
temperature for 3 days. The mixture was then diluted with diethyl ether
and filtered to remove the white precipitate. The filtrate was then
concentrated by distillation of the solvents at atmospheric pressure. The
solid residue from the filtration was combined with the solid residue
from the distillation, and partitioned between water and DCM. The aqueous
phase was extracted with DCM and the combined organic solutions were
dried (MgSO4), filtered, and the filtrate was treated with
m-chloroperbenzoic acid (commercially available, for example, from
Aldrich) (1 g, 57-86% pure, at least 3 mmol) and the mixture was stirred
at room temperature overnight. The reaction mixture was diluted with DCM
and washed with sodium bicarbonate solution. The organic solution was
washed with aqueous sodium metabisulfite solution (×2), aqueous
sodium bicarbonate solution, dried (MgSO4) and evaporated under
reduced pressure. The residue (790 mg) was dissolved in DCM and applied
to a silica cartridge (20 g) eluting with a gradient of
diethylether-petroleum ether (40-60° C.) (20%-60%) to give the
title compound (260 mg, 6%): 1H NMR δ (CDCl3) 3.71 (2H,
t, J=7 Hz), 3.15 (2H, t, J=7 Hz), 3.04 (2H, q, J=7 Hz), 2.40-2.30 (2H,
m), 1.44 (3H, t, J=7 Hz).

[0299]3-(Ethylthio)butyl methanesulfonate (for example, as prepared for
Intermediate 28) (360 mg, 1.70 mmol) was dissolved in DCM (10 ml) with
stirring. The solution was treated with m-chloroperbenzoic acid
(commercially available, for example, from Aldrich) (57-86%, 0.90 g, at
least 3 mmol), and the mixture was stirred at room temperature for 2.5 h.
Excess m-chloroperbenzoic acid was quenched by the addition of aqueous
sodium metabisulfite. Saturated aqueous sodium hydrogen carbonate and
further DCM were added. The mixture was shaken, the layers were
separated, and the aqueous was extracted with further DCM. The combined
DCM extracts were washed with further saturated aqueous sodium hydrogen
carbonate (×3), dried (MgSO4), and were concentrated in vacuo
to give the title compound as a colourless gum (393 mg, 95%): LCMS
RT=1.64 min, ES+ve m/z 262 (M+NH4).sup.+

[0300]6-Butyl-8-(4-piperidinyloxy)quinoline (for example, as prepared for
Intermediate 4) (2.44 g, 8.59 mmol) was stirred with
2-(2-bromoethyl)-1H-isoindole-1,3(2H)-dione (commercially available, for
example, from Acros and/or Aldrich) (2.40 g, 9.4 mmol) and potassium
carbonate (5.9 g, 43 mmol) in 2-butanone (75 ml) under nitrogen at
80° C. for 3 days. Further
2-(2-bromoethyl)-1H-isoindole-1,3(2H)-dione (2.4 g, 9.4 mmol) was added
and the heating and stirring were continued for a further 24 h. More
2-(2-bromoethyl)-1H-isoindole-1,3(2H)-dione (1.2 g, 4.7 mmol) was added
and the heating and stirring were continued for a further 24 h. The
mixture was cooled and partitioned between water and DCM. The aqueous
layer was extracted with more DCM (×2) and the combined organic
layers were washed with water, dried (MgSO4) and evaporated to an
oil. This oil was re-dissolved in DCM and loaded onto a column of silica
gel (250 g) that had been preconditioned with DCM. The column was eluted
with DCM, then DCM-ethanol-0.88 s.g. aqueous ammonia solution (200:8:1)
to give the title compound (2.76 g, 6.03 mmol). LCMS RT=2.91 min, ES+ve
m/z 458 [M+H].sup.+.

[0301]6-Butyl-8-(4-piperidinyloxy)quinoline (for example, as prepared for
Intermediate 4) (437 mg, 1.54 mmol) was stirred with 1,1-dimethylethyl
(3-bromopropyl)carbamate (commercially available, for example, from
Aldrich) (612 mg, 2.57 mmol) and potassium carbonate (426 mg, 3.15 mmol)
in 2-butanone (15 ml) under nitrogen at 80° C. overnight. The
mixture was cooled and partitioned between water and DCM. The aqueous
layer was extracted with more DCM (×2) and the combined organic
layers were washed with brine, dried (MgSO4) and evaporated to give
a yellow gum. This was purified by flash chromatography (50 g), eluting
with 0-30% methanol (containing 1% triethylamine) in DCM. The relevant
fractions were concentrated in vacuo to give the title compound as a
yellow oil (530 mg, 78%). LCMS RT=2.94 min, ES+ve m/z 442 [M+H].sup.+.

[0303]This was prepared in an analogous manner to that disclosed for
Intermediate 31 using 6-butyl-8-(4-piperidinyloxy)quinoline (for example,
as prepared for Intermediate 4) and 1,1-dimethylethyl
(4-bromobutyl)carbamate (commercially available, for example, from
Aldrich) instead of 1,1-dimethylethyl (3-bromopropyl) carbamate.

[0304]Thus, for example, 6-butyl-8-(4-piperidinyloxy)quinoline (for
example, as prepared for Intermediate 4) (855 mg, 3.0 mmol) was stirred
with 1,1-dimethylethyl (4-bromobutyl)carbamate (commercially available,
for example, from Fluka) (1.12 g, 4.5 mmol) and potassium carbonate (887
mg, 6.4 mmol) in 2-butanone (30 ml) under nitrogen at 80° C.
overnight. The mixture was cooled and concentrated in vacuo. The residue
was partitioned between water (25 ml) and DCM (25 ml). The aqueous layer
was extracted with more DCM (25 ml), and the combined organic layers
dried (hydrophobic frit) and concentrated in vacuo. The residue was
purified by flash chromatography (silica, 100 g), eluting with 0-15%
methanol (containing 1% triethylamine) in DCM over 40 min. The relevant
fractions were concentrated in vacuo to give the title compound as a
yellow gum (1.29 g, 94%). LCMS RT=3.04 min, ES+ve m/z 456 [M+H].sup.+.

[0306]This was prepared in an analogous manner to that disclosed for
Intermediate 31 using 6-pentyl-8-(4-piperidinyloxy)quinoline (for
example, as prepared for Intermediate 8) and 1,1-dimethylethyl
(3-bromopropyl) carbamate (commercially available, for example, from
Aldrich) with a reaction time of 7 h. LCMS RT=3.16 min, ES+ve m/z 456
[M+H].sup.+.

Intermediate 35

(2-{4-[(6-Butyl-8-quinolinyl)oxy]-1-piperidinyl}ethyl)amine

[0307]2-(2-{4-[(6-Butyl-8-quinolinyl)oxy]-1-piperidinyl}ethyl)-1H-isoindol-
e-1,3(2H)-dione (for example, as prepared for Intermediate 30) (2.76 g,
6.03 mmol) was stirred under nitrogen in ethanol (40 ml) containing
hydrazine monohydrate (commercially available, for example, from Aldrich)
(0.71 ml, 15.1 mmol) at 80° C. for 2 h. The reaction was cooled
with ice-water and filtered. The filter-cake was leached with ethanol and
the combined filtrates were evaporated to an oil containing a white
solid. This solid was mixed with DCM (about 20 ml) and filtered. The
filter-cake was leached with more DCM and the combined filtrates were
evaporated to give the title compound (2.07 g) as an oil: LCMS RT=2.32
min, ES+ve m/z 328 [M+H].sup.+.

Intermediate 36

(3-{4-[(6-Butyl-8-quinolinyl)oxy]-1-piperidinyl}propyl)amine

[0308]1,1-Dimethylethyl(3-{4-[(6-butyl-8-quinolinyl)oxy]-1-piperidinyl}pro-
pyl)carbamate (for example, as prepared for Intermediate 31) (493 mg, 1.12
mmol) was treated with a solution of hydrogen chloride in dioxane (4 M,
10 ml), and stirred under nitrogen overnight at room temperature. The
mixture was concentrated in vacuo. The residue was dissolved in methanol,
and applied to a SCX-2 ion exchange cartridge (10 g) which had been
preconditioned with methanol. The cartridge was washed with methanol (100
ml), and then eluted with 10% aqueous 0.88 s.g. ammonia in methanol (100
ml). The relevant basic fractions were concentrated in vacuo to give the
title compound (292 mg, 76%). LCMS RT=1.92 min, ES+ve m/z 342
(M+H).sup.+.

Intermediate 37

4-{4-[(6-Butyl-8-quinolinyl)oxy]-1-piperidinyl}butyl)amine

##STR00032##

[0310]This was prepared in an analogous manner to that disclosed for
Intermediate 36, using 1,1-dimethylethyl
(4-{4-[(6-butyl-8-quinolinyl)oxy]-1-piperidinyl}butyl)carbamate (for
example, as prepared for Intermediate 32).

[0311]Thus, for example, 1,1-dimethylethyl
(4-{4-[(6-butyl-8-quinolinyl)oxy]-1-piperidinyl}butyl) carbamate (for
example, as prepared for Intermediate 32) (1.29 g, 2.84 mmol) was
dissolved in MeOH (10 ml) and treated with a solution of hydrogen
chloride in dioxane (4 M, 30 ml). The mixture was stirred under nitrogen
for 3 h at room temperature. The mixture was concentrated in vacuo. The
residue was dissolved in methanol, and applied to a SCX-2 ion exchange
cartridge (50 g, pre-conditioned with methanol). The cartridge was washed
with methanol (3 column volumes), and then eluted with 10% aqueous 0.88
s.g. ammonia in methanol (3 CV). The relevant basic fractions were
concentrated in vacuo to give the title compound as a yellow gum (891 mg,
88%). LCMS RT=2.34 min, ES+ve m/z 356 [M+H].sup.+.

Intermediate 38

(5-{4-[(6-Butyl-8-quinolinyl)oxy]-1-piperidinyl}pentyl)amine

[0312]This was prepared in an analogous manner to that disclosed for
Intermediate 36, using 1,1-dimethylethyl
(5-{4-[(6-butyl-8-quinolinyl)oxy]-1-piperidinyl}pentyl)carbamate (for
example, as prepared for Intermediate 33). LCMS RT=2.28 min, ES+ve m/z
370 [M+H].sup.+.

Intermediate 39

(3-{4-[(6-Pentyl-8-quinolinyl)oxy]-1-piperidinyl}propyl)amine

[0313]This was prepared in an analogous manner to that disclosed for
Intermediate 36, using 1,1-dimethylethyl
(3-{4-[(6-pentyl-8-quinolinyl)oxy]-1-piperidinyl}propyl)carbamate (for
example, as prepared for Intermediate 34). LCMS RT=2.56 min, ES+ve m/z
356 [M+H].sup.+.

Intermediate 40

4-[(Ethylsulfonyl)amino]butyl ethanesulfonate

##STR00033##

[0315]4-Amino-1-butanol (commercially available, for example, from
Aldrich) (0.97 g, 11 mmol) was dissolved in DCM (50 ml) together with
triethylamine (9.0 ml, 65 mmol), and the stirred solution was cooled to
approximately 5° C. in an external ice-water bath under a nitrogen
atmosphere. Ethanesulfonyl chloride (commercially available, for example,
from Aldrich) (4.09 g, 31.8 mmol), dissolved in DCM (30 ml), was added
dropwise, using further DCM (20 ml) to wash in. The reaction mixture was
stirred under nitrogen and allowed to warm gradually to room temperature
over 4 h. The mixture was diluted with further DCM (100 ml) and washed
with saturated aqueous sodium hydrogen carbonate (100 ml). The aqueous
layer was extracted with further DCM (100 ml,×2). The combined
organic solutions were dried (MgSO4) and concentrated in vacuo to
give the crude product, which was used without further purification in
the reaction below (3.11 g): LCMS RT=2.06 min, ES+ve m/z 274 (M+H).sup.+,
291 (M+NH4).sup.+.

[0316]On another occasion, a portion of the crude material from an
analogous reaction was purified by chromatography. The brown oil (792 mg)
was applied to a silica cartridge (50 g, Flashmaster 2), eluting with
0-100% EtOAc-DCM over 40 min to give the pure title compound as a
colourless gum (621 mg): LCMS RT=2.15 min, ES+ve m/z 291
(M+NH4).sup.+.

Intermediate 41

3-Chloro-N-(1,1-dimethylethyl)-1-propanesulfonamide

[0317]To a solution of 3-chloropropanesulfonyl chloride (commercially
available, for example, from Aldrich) (1 g, 6 mmol) in DCM (10 ml) in an
ice-water bath was added t-butylamine (commercially available, for
example, from Aldrich) (1.3 ml, 12 mmol). The solution was allowed to
warm to ambient temperature and stirred for 3 h. The reaction mixture was
applied to a SCX-2 cartridge (50 g) (preconditioned with methanol) and
the cartridge eluted with methanol (2 column volumes). The methanol
fraction was concentrated in vacuo to give the title compound as a white
waxy solid (1.17 g, 97%). LCMS RT=2.61 min, ES+ve m/z 214 (M+H).sup.+.

[0321]A mixture of 6-butyl-8-(4-piperidinyloxy)quinoline (for example, as
prepared for Intermediate 4) (35 mg, 0.12 mmol) sodium bicarbonate (50
mg, 0.6 mmol) in DMF (1 ml) was treated with ethyl vinyl sulfone
(commercially available, for example, from Aldrich) (0.6 ml, 5.7 mmol)
and the suspension was heated to 100° C. for 15 min in a Smith
Creator® microwave oven. The mixture was diluted with methanol and
applied to an SCX-2 cartridge (10 g) eluting with methanol, followed by
10% aqueous 0.88 s.g. ammonia in methanol. The ammoniacal fractions were
evaporated under reduced pressure; the residue was dissolved in methanol
and re-evaporated. The residue (43 mg) was purified by MDAP and the
appropriate fractions were combined and evaporated under reduced pressure
to give the formate salt of the title compound (34 mg). The formate salt
was then dissolved in methanol (10 ml) and treated with 1.25 M hydrogen
chloride in methanol (0.2 ml, 0.25 mmol) and the solvent removed in vacuo
to give the title compound (37 mg): LCMS RT=2.71 min, ES+ve m/z 405
(M+H).sup.+.

[0325]A mixture of 6-butyl-8-(4-piperidinyloxy)quinoline (for example, as
prepared for Intermediate 4) (80 mg, 0.28 mmol), sodium iodide (30 mg,
0.2 mmol) and sodium bicarbonate (110 mg, 1.3 mmol) in DMF (2 ml) was
treated with a solution of mixture of 3-bromopropyl methyl sulfone and
3-chloropropyl methyl sulfone (for example, as prepared for Intermediate
19) (124 mg) in DMF (0.5 ml) and the mixture was heated at 150° C.
for 15 min in a Smith Creator® microwave oven. The reaction mixture
was applied to an SCX-2 cartridge (10 g), preconditioned with methanol,
and eluted with methanol, followed by 10% aqueous 0.88 s.g. ammonia in
methanol. The ammoniacal fractions were combined and concentrated in
vacuo and the residue (126 mg) was purified by MDAP. Appropriate
fractions were combined and concentrated in vacuo and the residue (30 mg)
was applied to an SCX-2 cartridge (5 g), pre-conditioned with methanol
and eluted with methanol, followed by 10% aqueous 0.88 s.g. ammonia in
methanol. The ammoniacal fractions were combined and concentrated in
vacuo to give the free base of the title compound (21 mg, 18%): This was
treated with 1.25 M hydrogen chloride solution in methanol (0.15 ml) and
the solution was evaporated in vacuo to give the title compound (22 mg,
89%): LCMS RT=2.49 min, ES+ve m/z 405 (M+H).sup.+.

[0330]A mixture of 6-butyl-8-(4-piperidinyloxy)quinoline (for example, as
prepared for Intermediate 4) (284 mg, 1.00 mmol), sodium iodide (150 mg,
1.0 mmol) and sodium bicarbonate (700 mg, 8 mmol) was treated with a
solution of a mixture of 3-bromopropyl propyl sulfone and 3-chloropropyl
propyl sulfone (for example, as prepared for Intermediate 18) (4:3, 494
mg) in DMF (6 ml) and the mixture was heated at 100° C. for 18 h
under nitrogen. The reaction mixture was allowed to cool to room
temperature and partitioned between EtOAc and water. The organic phase
was washed with water (×4), brine, dried (MgSO4), and
evaporated in vacuo. The residue (681 mg) was dissolved in methanol and
applied to an SCX-2 cartridge (50 g) eluting with methanol, followed by
10% aqueous 0.88 s.g. ammonia in methanol. The ammoniacal fractions were
combined and evaporated in vacuo. The residue (0.51 g) was dissolved in
DCM and purified by chromatography on Flashmaster 2 (silica, 70 g
cartridge) eluting with 0-15% methanol (containing 1% triethylamine) in
DCM over 40 min. The appropriate fractions were combined and evaporated
and the residue (183 mg) was further purified by MDAP to give the formate
salt of the title compound (132 mg, 27%): LCMS RT=2.70 min, ES+ve m/z 433
(M+H).sup.+. The formate salt (132 mg, 0.3 mmol) was dissolved in
methanol (3 ml) and treated with 1.25 M hydrogen chloride in methanol
(0.5 ml). The solvent was removed in vacuo to give the title compound
(127 mg, 84%) LCMS RT=2.71 min, ES+ve m/z 433 (M+H).sup.+.

[0340]A mixture of 6-butyl-8-(4-piperidinyloxy)quinoline (for example, as
prepared for Intermediate 4) (88 mg, 0.31 mmol), sodium hydrogen
carbonate (183 mg, 2.18 mmol) and sodium iodide (92 mg, 0.61 mmol) in DMF
(3 ml) was treated with 3-(ethylsulfonyl)butyl methanesulfonate (for
example, as prepared for Intermediate 29) (143 mg, 0.59 mmol) and the
suspension was heated to 150° C. for 30 min in a Smith Creator®
microwave oven. The mixture was diluted with methanol and applied to an
SCX-2 cartridge (50 g) eluting with methanol, followed by 10% aqueous
0.88 s.g. ammonia in methanol. The relevant fractions were concentrated,
and the residue was purified by MDAP. The appropriate fractions were
combined and concentrated in vacuo to give the title compound as the
monoformate salt (68 mg, 46%): LCMS RT=2.72 min, ES+ve m/z 433
(M+H).sup.+; A portion of this material (12 mg) was dissolved in methanol
and treated with 1.25 M hydrogen chloride in methanol (0.5 ml, excess).
The volatiles were removed under a stream of nitrogen to give the title
compound (13 mg) as a pale yellow glass: LCMS RT=2.68 min, ES+ve m/z 433
(M+H).sup.+.

[0342]A mixture of 6-pentyl-8-(4-piperidinyloxy)quinoline (for example, as
prepared for Intermediate 8) (72 mg, 0.24 mmol), sodium hydrogen
carbonate (144 mg, 1.7 mmol), sodium iodide (30 mg, 0.2 mmol) and
3-(ethylsulfonyl)propyl 4-methylbenzenesulfonate (for example, as
prepared for Intermediate 16) (68 mg, 0.2 mmol) in DMF (2 ml) was heated
to 150° C. for 15 min in a Smith Creator® microwave oven. The
mixture was applied to an SCX-2 cartridge (20 g) eluting with methanol,
followed by 10% aqueous 0.88 s.g. ammonia in methanol. The relevant
fractions were concentrated, and the residue was applied to a silica
cartridge (50 g), eluting with DCM-ethanol-aqueous 0.88 s.g. ammonia
(200:8:1 then 100:8:1). One fraction contained clean product, but the
material obtained from concentration of a second fraction required
further purification by MDAP. The relevant fractions from the MDAP
purification were concentrated in vacuo and combined with the pure
material from the earlier purification. This material (12 mg) was
dissolved in methanol and treated with 1.25 M hydrogen chloride in
methanol (0.5 ml, excess). The volatiles were removed under a stream of
nitrogen to give the title compound (36 mg, 30%): LCMS RT=2.89 min, ES+ve
m/z 433 (M+H).sup.+.

[0346]To a solution of 6-butyl-8-(4-piperidinyloxy)quinoline (for example,
as prepared for Intermediate 4) (0.15 g, 0.53 mmol) in THF (5 ml) was
added 2,3-dihydrothiophene 1,1-dioxide (commercially available, for
example, from AKOS) (0.150 g, 1.27 mmol). The solution was heated to
80° C. for 2.5 h. To the solution at ambient temperature was added
a further amount of 2,3-dihydrothiophene 1,1-dioxide (0.150 g, 1.27 mmol)
and the solution stirred overnight at ambient temperature. The solution
was heated to reflux for 2 h and then at ambient temperature for 7 days.
The reaction was applied to an SCX-2 cartridge (20 g), preconditioned
with methanol, and the cartridge washed with methanol (2 column volumes).
The cartridge was eluted with 10% 0.880 s.g. ammonia in methanol (2
column volumes) and the basic fractions concentrated in vacuo. The
residue was purified by MDAP and the appropriate fractions combined and
evaporated. The combined fractions were applied to an SCX-2 cartridge (20
g), preconditioned with methanol, and the cartridge washed with methanol.
The cartridge was eluted with 10% 0.88 s.g. ammonia in methanol (2 column
volumes) and the basic fractions concentrated in vacuo to give the title
compound (17 mg, 8%). LCMS RT=2.59 min, ES+ve m/z 403 (M+H).sup.+.

[0352](2-{4-[(6-Butyl-8-quinolinyl)oxy]-1-piperidinyl}ethyl)amine (for
example, as prepared for Intermediate 35) (50 mg, 0.15 mmol) was stirred
with triethylamine (0.1 ml, 0.7 mmol) in DCM (2 ml) at room temperature
under nitrogen and benzenesulphonyl chloride (commercially available, for
example, from Aldrich) (29 μL, 0.22 mmol) was added. After 20 min,
LCMS showed the reaction was complete. The solution was poured onto a
Bond Elute silica cartridge (10 g), preconditioned with DCM. The
cartridge was eluted with this solvent, and then DCM-ethanol-0.88 s.g.
aqueous ammonia solution (200:8:1) to give, after evaporation, the crude
free base of the title compound (55 mg). This was dissolved in
dimethylsulfoxide-methanol (1:1; 1 ml) and purified by MDAP to give,
after evaporation, the formate salt of the title compound: LCMS RT=2.96
min, ES+ve m/z 468 (M+H).sup.+. 1.25 M hydrogen chloride in methanol
(0.75 ml, excess) was added to this material and the solution was
evaporated to dryness and dried to give the title compound (39 mg, 48%):
LCMS RT=2.95 min, ES+ve m/z 468 (M+H).sup.+.

[0354](3-{4-[(6-Butyl-8-quinolinyl)oxy]-1-piperidinyl}propyl)amine (for
example, as prepared for Intermediate 36) (30 mg, 0.09 mmol) was
dissolved in DCM (1 ml), and treated with triethylamine (38 μl, 0.27
mmol), and ethanesulfonyl chloride (commercially available, for example,
from Aldrich) (17 μl, 0.18 mmol). The mixture was stirred in a
stoppered vial at room temperature for 1 h, then left to stand at room
temperature overnight. The mixture was diluted with methanol and applied
to an SCX-2 cartridge (5 g) eluting with methanol, followed by 10%
aqueous 0.88 s.g. ammonia in methanol. The relevant fractions were
concentrated, and the residue was purified by MDAP. The appropriate
fractions were combined and concentrated to give the title compound as
the monoformate salt (29 mg, 67%): LCMS RT=2.62 min, ES+ve m/z 434
(M+H).sup.+. The material was dissolved in methanol and treated with 1.25
M hydrogen chloride in methanol (excess). The volatiles were removed
under a stream of nitrogen to give the title compound (30 mg): LCMS
RT=2.63 min, ES+ve m/z 434 (M+H).sup.+.

[0358](3-{4-[(6-Butyl-8-quinolinyl)oxy]-1-piperidinyl}propyl)amine (for
example, as prepared for Intermediate 36) (30 mg, 0.09 mmol) was
dissolved in DCM (1 ml), and treated with triethylamine (38 μl, 0.27
mmol), and 2-propanesulfonyl chloride (commercially available, for
example, from Aldrich) (20 μl, 0.18 mmol). The mixture was stirred in
a stoppered vial at room temperature for 1 h, then left to stand at room
temperature overnight. LCMS analysis indicated that reaction was not
complete. Further triethylamine (38 μl, 0.27 mmol), and
2-propanesulfonyl chloride (17 μl, 0.18 mmol) were added and the
mixture stirred at room temperature for 1.5 h. LCMS analysis indicated
that reaction was still not complete. Further triethylamine (19 μl,
0.14 mmol), and 2-propanesulfonyl chloride (10 μl, 0.09 mmol) were
added and the mixture stirred at room temperature overnight. The mixture
was diluted with methanol and applied to an SCX-2 cartridge (5 g) eluting
with methanol, followed by 10% aqueous 0.88 s.g. ammonia in methanol. The
relevant fractions were concentrated, and the residue was purified by
MDAP. The appropriate fractions were combined and concentrated, but the
product was found to contain an impurity, thought to be
(3-{4-[(6-butyl-8-quinolinyl)oxy]-1-piperidinyl}propyl)sulfamic acid. The
material was dissolved in methanol and applied to an aminopropyl
cartridge (5 g) eluting with methanol. The relevant fractions were
combined and concentrated to give the title compound as the free base:
LCMS RT=2.68 min, ES+ve m/z 448 (M+H).sup.+. The material was dissolved
in methanol and treated with 1.25 M hydrogen chloride in methanol (0.5
ml, excess). The volatiles were removed under a stream of nitrogen to
give the title compound (13 mg, 27%): LCMS RT=2.80 min, ES+ve m/z 448
(M+H).sup.+.

[0370]Under nitrogen, 6-chloro-8-fluoroquinoline (for example, as prepared
for Intermediate 5) (4.6 kg, 1.0 eqv) was added to N-methylpyrrolidinone
(46 L, 10 vol). To this mixture, ferric acetylacetonate (0.89 kg, 0.1
eqv) was added and the reaction mass cooled to 0 to -10° C. A
solution of n-butyl magnesium chloride (commercially available, for
example, from Aldrich) (14.84 L, 1.35 eqv of 2.3M grignard in
tetrahydrofuran) was added slowly over approximately 4 hours at between 0
to -10° C. and the reaction was stirred for 10 to 20 min. The
progress of the reaction was monitored by HPLC. As there was more than 2%
starting material a further portion of n-butyl magnesium chloride was
added (0.52 L, 0.05 eqv of 2.3M grignard in tetrahydrofuran) at 0 to
-10° C. over 10 to 30 min. After passing the HPLC (starting
material not more than 2%), the reaction mixture was quenched with
ammonium chloride solution (4.6 kg, 1 wt, in 101 L water) keeping the
temperature below 35° C., an the reaction mixture was stirred at
approximately 27° C. for 15-30 min. A dilute solution of aqueous
HCl (3.5 vol, 14.6 L [made up as bulk solution of 4.6 L 35% HCl in 13.8 L
water]) was then added into the reaction mixture until pH 1-2 was
reached. The reaction mass was extracted at pH 1 to 2 with ethyl acetate
(46 L, then 28 L×3). The combined organic layers were then washed
with water (69 L, 15 vol) and dilute ammonia solution (46 L [41.4 L water
and 4.6 L 22.38% aqueous ammonia solution). The organic layer was washed
with water (55.2 L×3), the organic layer was separated and
concentrated in vacuo (vacuum no less than 600 mm Hg), keeping the
temperature below 70° C. Toluene (4.6 L, 1 vol) was then added and
the mixture concentrated in vacuo (vacuum no less than 600 mm Hg),
keeping the temperature below 70° C. to a crude oil to remove
traces of ethyl acetate. The residue was diluted in toluene (6.9 L, 1.5
vol) and added to n-hexane (138 L, 30 vol) with stirring at 25-35°
C. After 1 to 2 hr, the mass was filtered through celite (4.6 kg) and the
celite bed was washed with mixture of toluene and hexane (1:10, 0.92 L,
0.2 vol toluene and 9.2 L, 2 vol hexane) followed by hexane washing (46
L, 10 vol). The combined filtrate was stirred with silica gel (6.9 kg,
1.5 wt) for 1.5 to 2.5 hr at 25-35° C. Silica gel was filtered off
and filtered silica gel was washed with a mixture of hexane and
triethylamine (20:1 mixture, 5×48.3 L). The combined filtrate was
then concentrated twice in vacuo (vacuum not less than 600 mm Hg) keeping
the temperature below 70° C. Toulene (4.6 L, 1 vol) was then added
to the residue (approximately 10 L) and again concentrated in vacuo
(vacuum not less than 650 mm Hg) keeping the temperature below 70°
C. to remove traces of solvent (toluene less than 10%). The residue was
cooled, unloaded and stored under nitrogen. The title compound was
obtained in 82.5% yield (4.25 kg) and in 99.0% purity.

[0373]Under a nitrogen atmosphere, N-Boc-4-hydroxypiperidine (commercially
available, for example, from Aldrich) (11.66 kg, 1.5 eqv) and sodium
tert-butoxide (5.5 kg, 1.5 eqv) was charged into a reactor containing
N-methylpyrrolidinone (39.25 L, 5 vol) and stirred at approximately
25° C. to obtain a clear solution. In another reactor under a
nitrogen atmosphere was charged 6-butyl-8-fluoroquinoline (for example,
as obtained from Stage 1) (7.85 kg, 1.0 eqv) and N-methylpyrrolidinone
(31.4 L, 4 vol) under nitrogen and heated to approximately 110° C.
over 1-3 hr. From the first reactor, the solution of
N-Boc-4-hydroxypiperidine sodium salt in N-methylpyrrolidinone was added
slowly over 2-3 hr into the second reactor containing
6-butyl-8-fluoroquinoline in N-methylpyrrolidinone at approximately
110° C. The reaction mixture was stirred for approximately 1 hr at
approximately 110° C. and progress of the reaction was monitored
by HPLC (starting material not more than 2%). After completion of
reaction, the temperature was adjusted to 30-40° C. and a
saturated solution of ammonium chloride (7.85 kg ammonium chloride in 157
L water, 20 vol) was added into the reaction mass below 40° C. To
this reaction mixture, ethyl acetate (78.5 L, 10 vol) was added followed
by acetic acid (1.15 L, 0.15 vol) and stirred well. The organic layer was
separated, and aqueous layer was again extracted with ethyl acetate
(39.25 L, 5 vol). The combined organics were then washed with water (78.5
L, 10 vol×3). The combined organics were concentrated in vacuo
(vacuum not less than 600 mm Hg), keeping the temperature below
60° C. To the concentrated reaction mass, toluene (23.55 L, 3 vol)
was added, and the reaction mixture concentrated in vacuo (vacuum not
less than 600 mm Hg), keeping the temperature below 60° C. To this
crude mass again fresh toluene (78.5 L, 10 vol) was added, followed by
22.8% HCl in iso-propyl alcohol (24.51 L, 3.36 eqv), and reaction mixture
was stirred at 70-80° C. for 1-2 hr. The progress of the reaction
was monitored by HPLC (starting material less than 2% by HPLC). After
completion of reaction, the reaction was cooled to 30-40° C. and
water (78.5 L, 10 vol) was added portionwaise into the reaction mixture,
stirred well and the layers separated. The aqueous layer was washed three
times with dichloromethane (78.5 L, 10 vol, then 54.95 L, 7 vol, then
39.25 L, 5 vol). The aqueous layer was slowly basified with sodium
hydroxide solution (7.85 kg in 54.95 L water) until pH was 12.5 to 13.5.
The product was extracted in dichloromethane (78.5 L, 10 vol, then 39.25
L, 5 vol, ×2). The combined dichloromethane layers were washed with
aqueous sodium chloride solution (7.85 kg in 78.5 L water, ×3). The
combined organics were concentrated in vacuo (vacuum no less than 600 mm
Hg) keeping the temperature below 50° C. In order to remove traces
if dichloromethane, N,N'-dimethylformamide (23.6 L, 3 vol) was added and
the reaction mass was held at a vacuum of no less than 650 mm Hg, keeping
the temperature below 50° C. The title compound (3.76 kg, 34.24%
yield) was obtained as solution in N,N'-dimethylformamide and stored at
approximately 5° C.

[0376]To a solution of 4-aminobutanol (commercially available, for
example, from Aldrich) (2.6 kg, 1 eqv) in toluene (65 L, 25 vol) at
25-35° C. was added phthalic anhydride (commercially available,
for example, from Aldrich) (4.3 kg, 1 eqv). The temperature of the
reaction mixture was slowly raised to 80-90° C. for 2-3 hr and
then heated to reflux to azeotropically remove the water from the
reaction mass. The progress of the reaction was monitored by TLC, and
after passing the TLC (starting material not more than 2%), approximately
25-40% of toluene was removed from reaction by atmospheric distillation.
The reaction mass was then cooled to 0-5° C. and triethylamine
(4.4 kg, 1.5 eqv) was charged to the reaction mass over 15 min. Ethane
sulphonyl chloride (commercially available, for example, from Aldrich)
(4.5 kg, 1.2 eqv) diluted in toluene (7.8 L, 3 vol) was slowly added into
the reaction mass at 0-5° C. under a nitrogen atmosphere. The
reaction mixture was stirred for approximately 2 hr, then monitored by
HPLC (starting material not more than 2%). After completion of reaction,
water (26 L, 10 vol) and triethylamine (2.6 kg, 1 vol) was added to the
reaction mass, and stirred at 30-35° C. for 10-30 min, and then
filtered over celite (1.3 kg, 0.5 wt, pre-conditioned with toluene, 2.6
L, 1 vol). The celite was then washed with hot toluene (40-50° C.,
10.4 L, 4 vol), and the organic layer was separated. The aqueous layer
was extracted with toluene (7.8 L, 3 vol) and combined organic layers
were then washed with aqueous sodium bicarbonate solution (2.6 kg in 26 L
water) and water (13 L, 5 vol). The organic layer was concentrated in
vacuo (vacuum no less than 600 mm Hg), keeping the temperature below
70° C. Iso-propylalcohol (7.8 L, 3 vol) was added and the reaction
mass was concentrated in vacuo (vacuum no less than 600 mm Hg), keeping
the temperature below 70° C. To this concentrated mass,
iso-propylalcohol (26 L, 10 vol) was added, and warmed to 50-60°
C. to give a clear solution. This solution was cooled to 35-45° C.
and n-hexane (26 L, 10 vol) was added slowly and then cooled to
25-35° C. The reaction mass was stirred for 1.5 to 2.5 hr and
filtered by centrifugation. The wet cake was washed with n-hexane (31 L,
11.9 vol) and filtered again by centrifugation. The material was dried in
vacuo (vacuum no less than 650 mm Hg) for 10-12 hr at 50-55° C.
The title compound was isolated in 78.36% yield (7.1 kg) and 99.6%
purity.

[0379]To a solution of 6-butyl-8-(4-piperidinyloxy)quinoline (for example,
as prepared for Intermediate 4 in stages 2a and 2b) (3.76 kg, 1 eqv) in
N,N'-dimethylformamide (7.52 L, 2 vol) was added tetrabutylammonium
iodide (commercially available, for example, from Aldrich) (0.019 kg,
0.005 wt), sodium iodide (1.98 kg, 1 eqv), diisopropylethylamine (3.42
kg, 2 eqv), and 4-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)butyl
ethanesulfonate (for example, as prepared for Intermediate 45 in stages
3a and 3b) (4.32 kg, 1.1 eqv) under nitrogen atmosphere at 25-35°
C. The reaction mass was warmed to about 70-80° C. and maintained
at that temperature for 10-12 hr. The reaction was monitored by HPLC
(starting material not more than 1.5%). After the completion of reaction,
the reaction mixture was cooled to 30-40° C. The reaction mixture
was diluted with water (37.6 L, 10 vol) followed by toluene (37.6 L, 10
vol). To the reaction mixture was then added activated carbon (0.38 kg,
0.1 wt) and celite (0.94 kg, 0.25 wt) and warmed to 50-60° C. for
15-30 min. The reaction mixture was stirred and cooled to 25-35°
C., then filtered over celite (celite bed made with 1 kg celite, 18.8 L
water, 5 vol). The celite bed was then washed with hot (50-60° C.)
toluene (18.8 L, 5 vol). The combined filtrates were separated and the
aqueous layer was extracted with toluene (18.8 L, 5 vol, ×3). The
combined organic layers were washed with water (37.6 L, 10 vol,
×3). The organic layer was washed with concentrated [37.36%]
aqueous HCl (22.56 L, 6 vol) and the aqueous HCI layer containing product
was collected. The aqueous HCI layer was then heated to reflux
(110-120° C.) and 5-10% of solvent was distilled off. Reflux was
then continued for a further 10-12 hr. An aliquot of sample was submitted
for HPLC (starting material not more than 2%), then the reaction mixture
was cooled to 5-15° C., stirred for 30-60 min, filtered in vacuo
and the filter cake was washed with cooled (5-15° C.) water (7.52
L, 2 vol). The resulting filtrate was basified by slow addition of sodium
hydroxide solution (19.5 L NaOH solution [made with 11.28 kg NaOH and
22.56 L water]) to pH 4-5. The aqueous layer was then washed with
dichloromethane/iso-propylalcohol (10:1, 41.36 L, 11 vol, then 20.68 L,
5.5 vol×2). The pH of the aqueous layer containing product was
slowly adjusted to pH 8 to 9 keeping the temperature at approximately
30° C. by adding sodium hydroxide solution (2 L NaOH solution
[made with 11.28 kg NaOH and 22.56 L water]). The aqueous layer was then
extracted with dichloromethane (37.6 L, 10 vol, then 18.8 L, 5 vol, then
11.28 L, 3 vol), and the combined organics were washed with a solution of
dilute ammonia (37.6 L ammonia solution [15.04 L ammonia (22.38%) and
22.56 L water]) and iso-propylalcohol (18.8 L, 5 vol), followed by dilute
ammonia (37.6 L ammonia solution, [15.04 L ammonia (22.38%) and 22.56 L
water]×2). 20-40% of dichloromethane solvent was removed by
distillation at atmospheric pressure. The remaining mixture was
concentrated in vacuo (vacuum no less than 650 mm Hg), keeping the
temperature below 40-45° C. The residue was diluted with
dichloromethane (1.88 L, 0.5 vol) and can be stored under nitrogen at
2-8° C. for up to 3 days. The title compound was isolated in
56.68% yield (2.57 kg) and 86% purity.

[0381]To a solution of
4-{4-[(6-butyl-8-quinolinyl)oxy]-1-piperidinyl}butyl)amine (for example,
as prepared for Intermediate 37 in stages 4a and 4b) (2.57 kg, 1.0 eqv)
was added dichloromethane (30.84 L, 12 vol), and triethylamine (2.05 kg,
2.8 eqv) under a nitrogen atmosphere. The reaction mixture was cooled to
0-5° C. and a solution of ethanesulphonyl chloride (commercially
available, for example, from Aldrich) (1.86 kg, 2.0 eqv) in
dichloromethane (7.71 L, 3 vol) was added dropwise at 0-10° C.
After stirring for 2-3 hr at 0-10° C. under nitrogen, the reaction
temperature was adjusted to 25-35° C. and stirred for 2-3 hr. A
sample was analysed by HPLC to monitor reaction progress. The reaction
mixture was quenched at 25-35° C. with water (25.7 L, 10 vol). The
organic layer was separated and the aqueous layer extracted with
dichloromethane (7.71 L, 3 vol). The combined organics were washed with
citric acid solution (5.14 kg, 2 wt dissolved in 25.7 L water, 10 vol).
The aqueous layer containing product was collected and the organic layer
was again washed with aqueous citric acid solution (0.77 kg, 0.3 wt,
dissolved in 3.34 L water, 1.3 vol) and the organic layer was separated.
The combined aqueous layers were washed with dichloromethane (12.8 L, 5
vol). Dilute ammonia solution (12.85 L ammonia (22.38%) dissolved in
12.85 L water) was then added to the aqueous layer keeping the
temperature at 30-35° C., until the pH reached was between 10-12.
The product from the aqueous layer was then extracted with
dichloromethane (25.7 L, 10 vol, then 7.71, 3 vol) and the combined
organics were again washed with dilute ammonia solution (5.14 L ammonia
(22.38%) dissolved in 5.14 L water). The organic layer was finally washed
twice with water (25.7 L, 10 vol) then 50-80% solvent was removed by
distillation under atmospheric pressure, keeping the temperature below
55° C. The reaction mixture was then concentrated in vacuo (vacuum
no less than 600 mm Hg) keeping the temperature below 50° C. To
this crude mixture, iso-propylalcohol (7.71 L, 3 vol) was added and
concentrated in vacuo (vacuum no less than 600 mm Hg) keeping the
temperature below 50° C. To this, methanol (17.99 L, 7 vol) and
activated carbon (0.13 kg, 0.05 wt) were added sequentially, and stirred
for 15-30 min. The charcoal was filtered over a celite bed (prepared
using 1.5 kg celite and 7.71 L methanol), then washed with methanol (7.71
L, 3 vol) and to the combined filtrate, HCl in iso-propylalcohol (22.8%,
3.6 L, 2.65 eqv) was added at 20-30° C., and stirred for 15-30
min. The reaction mass was then concentrated in vacuo (vacuum no less
than 650 mm Hg) until a syrup remained which started to solidify, then
methanol (12.85 L, 5 vol) was added to the residue to obtain a clear
solution. The reaction mass was then stirred at 30-35° C., and
ethyl acetate (51.4 L, 20 vol) was added. The reaction mass was then
stirred for 1-2 hr at 25-35° C. and then cooled to 5-10° C.
for 1-2 hr, then centrifuged. The solid was then washed with
methanol:ethyl acetate mixture (1:7, 2.57 L methanol in 17.99 L ethyl
acetate) at 5-10° C. and centrifuged. The product was dried in
vacuo (vacuum no less than 650 mm Hg) at 50-55° C. for 8-12 hrs.
The title compound was obtained in 53.15% yield (2 kg).

[0383]A solution of
N-(4-{4-[(6-butyl-8-quinolinyl)oxy]-1-piperidinyl}butyl)ethanesulfonamide-
, dihydrochloride salt (for example, as prepared for Example 23B in stage
5) (2 kg, 1 eqv) in methanol (8 L, 4 vol) at 25-35° C. was passed
through catridge filters (1 micron, followed by 0.2 micron frit) and the
line flushed with methanol (2 L, 1 vol). The filtrate was cooled to
25-30° C. and stirred for 30 min to ensure complete dissolution.
Ethyl acetate (4.4 L, 2.2 vol) was slowly added into the reaction
mixture, which was then seeded with
N-(4-{4-[(6-butyl-8-quinolinyl)oxy]-1-piperidinyl}butyl)ethanesulfonamide-
, dihydrochloride salt (0.0048 kg, 0.0024 wt) and aged isothermally for
30-45 min at 25-30° C. Further ethyl acetate (35.6 L, 17.8 vol)
was added slowly over 2-2.5 hr, keeping the temperature between
25-30° C., then stirred at this temperature for 30 min. The
reaction mixture was slowly cooled to 0-10° C., and stirred at
this temperature for an additional 2-3 hrs. The product was filtered
through a centrifuge and washed with pre-chilled (0-10° C.) ethyl
acetate (4 L, 2 vol). The cake was offloaded, spin-dried then dried in
vacuo (vacuum no less than 600 mm Hg) at 55-60° C. for 12-14 hrs
to give the title compound in 85.55% yield (1.72 kg) and 98.59% purity.

[0384]An XRPD pattern of
N-(4-{4-[(6-Butyl-8-quinolinyl)oxy]-1-piperidinyl}butyl)ethanesulfonamide-
, dihydrochloride salt (as prepared for Example 23B) is shown in FIG. 1
and FIG. 2. The peak angles and d-spacings for this form are tabulated
below:

[0386](4-{4-[(6-Butyl-8-quinolinyl)oxy]-1-piperidinyl}butyl)amine (for
example, as prepared for Intermediate 37) (36 mg, 0.1 mmol) was dissolved
in DCM (2 ml) with stirring, and treated with triethylamine (22 μl,
0.16 mmol), and 1-propanesulfonyl chloride (commercially available, for
example, from Aldrich) (14 μl, 0.12 mmol). The mixture was stirred at
room temperature for 1 h. The mixture was washed with saturated aqueous
sodium hydrogen carbonate, and the aqueous layer was extracted with
further DCM (×2) (hydrophobic frit). The combined organic solutions
were concentrated, and the residue was purified by MDAP. The appropriate
fractions were combined and concentrated to give the title compound as
the formate salt: LCMS RT=2.89 min, ES+ve m/z 462 (M+H).sup.+. The
material was dissolved in methanol and treated with 1.25 M hydrogen
chloride in methanol (0.6 ml, excess). The volatiles were removed in
vacuo to give the title compound (17 mg 32%): LCMS RT=2.88 min, ES+ve m/z
462 (M+H).sup.+.

[0388](4-{4-[(6-Butyl-8-quinolinyl)oxy]-1-piperidinyl}butyl)amine (for
example, as prepared for Intermediate 37) (87 mg, 0.24 mmol) was
dissolved in DCM (2 ml), and treated with triethylamine (167 μl, 1.2
mmol), and 2-propanesulfonyl chloride (commercially available, for
example, from Aldrich) (54 μl, 0.48 mmol). The mixture was stirred at
room temperature for 1.5 h. LCMS analysis indicated that reaction was not
complete. Further triethylamine (167 μl, 1.2 mmol), and
2-propanesulfonyl chloride (54 μl, 0.48 mmol) were added and the
mixture stirred at room temperature for 1 h. The reaction was quenched by
the addition of methanol then concentrated under a stream of nitrogen.
The residue was re-dissolved in methanol and applied to an SCX-2
cartridge (20 g) eluting with methanol, followed by 10% aqueous 0.88 s.g.
ammonia in methanol. The relevant fractions were concentrated, and the
residue was purified by MDAP. The appropriate fractions were combined and
concentrated, but the product was found to contain impurities, thought to
be (3-{4-[(6-butyl-8-quinolinyl)oxy]-1-piperidinyl}propyl)sulfamic acid.
The material was dissolved in methanol and applied to an aminopropyl
cartridge (5 g) eluting with methanol. The relevant fractions were
combined and concentrated to give the title compound as the free base (43
mg, 39%): LCMS RT=2.63 min, ES+ve m/z 462 (M+H).sup.+. Approximately half
the material was dissolved in methanol and treated with 1.25 M hydrogen
chloride in methanol (1 ml, excess). The volatiles were removed under a
stream of nitrogen to give the title compound (26 mg): LCMS RT=2.70 min,
ES+ve m/z 462 (M+H).sup.+.

[0390](4-{4-[(6-Butyl-8-quinolinyl)oxy]-1-piperidinyl}butyl)amine (for
example, as prepared for Intermediate 37) (39 mg, 0.11 mmol) was
dissolved in DCM (2 ml) with stirring, and treated with triethylamine (25
μl, 0.18 mmol), and isobutanesulfonyl chloride (commercially
available, for example, from Aldrich) (17 μl, 0.13 mmol). The mixture
was stirred at room temperature for 1 h, then treated with further
triethylamine (13 μl, 0.09 mmol), and isobutanesulfonyl chloride (13
μl, 0.10 mmol). The mixture was stirred at room temperature for a
further 30 min. The mixture was washed with saturated aqueous sodium
hydrogen carbonate, and the aqueous layer was extracted with further DCM
(×2) (hydrophobic frit). The combined organic solutions were
concentrated, and the residue was purified by MDAP. The appropriate
fractions were combined and concentrated to give the title compound as
the formate salt: LCMS RT=3.05 min, ES+ve m/z 476 (M+H).sup.+. The
material was dissolved in methanol and treated with 1.25 M hydrogen
chloride in methanol (0.6 ml, excess). The volatiles were removed under a
stream of nitrogen to give the title compound (11 mg, 18%): LCMS RT=3.02
min, ES+ve m/z 476 (M+H).sup.+.

[0392](4-{4-[(6-Butyl-8-quinolinyl)oxy]-1-piperidinyl}butyl)amine (for
example, as prepared for Intermediate 37) (74 mg, 0.2 mmol) was dissolved
in DCM (2 ml), and treated with triethylamine (55 μl, 0.4 mmol), and
cyclohexanesulfonyl chloride (commercially available, for example, from
Aldrich) (44 μl, 0.30 mmol). The mixture was stirred at room
temperature for 1 h. LCMS analysis indicated that reaction was not
complete. Further triethylamine (55 μl, 0.4 mmol), and
cyclohexanesulfonyl chloride (20 ml, 0.1 mmol) were added and the mixture
stirred at room temperature for overnight. The reaction was quenched by
the addition of methanol then concentrated under a stream of nitrogen.
The residue was re-dissolved in methanol and applied to an SCX-2
cartridge (20 g) eluting with methanol, followed by 10% aqueous 0.88 s.g.
ammonia in methanol. The relevant fractions were concentrated, and the
residue was purified by MDAP. The appropriate fractions were combined and
concentrated to give the title compound as the formate salt: LCMS RT=3.08
min, ES+ve m/z 502 (M+H).sup.+. The material was dissolved in methanol
and treated with 1.25 M hydrogen chloride in methanol (0.5 ml, excess).
The volatiles were removed under a stream of nitrogen to give the title
compound (26 mg, 23%): LCMS RT=3.06 min, ES+ve m/z 502 (M+H).sup.+.

[0394]This was prepared in an analogous manner to that disclosed for
Example 24 using
(4-{4-[(6-butyl-8-quinolinyl)oxy]-1-piperidinyl}butyl)amine (for example,
as prepared for Intermediate 37) (42 mg, 0.12 mmol), triethylamine (26
μl, 0.19 mmol), and cyclohexylmethanesulfonyl chloride (commercially
available, for example, from Array Biopharma) (39 mg, 0.20 mmol) in DCM
(2 ml). The title compound was initially obtained as the formate salt,
but required further purification. The salt was re-dissolved in methanol
and applied an SCX-2 cartridge (5 g) eluting with methanol, followed by
10% aqueous 0.88 s.g. ammonia in methanol. The relevant basic fractions
were concentrated in vacuo to provide the title compound as the free
base: LCMS RT=3.31 min, ES+ve m/z 516 (M+H).sup.+. The material was
dissolved in methanol and treated with 1.25 M hydrogen chloride in
methanol (1 ml, excess). The volatiles were removed under a stream of
nitrogen to give the title compound (26 mg, 37%): LCMS RT=3.29 min, ES+ve
m/z 516 (M+H).sup.+.

[0396]DMF (0.5 ml) was added to sodium hydride (60% dispersion in oil, 20
mg, 0.5 mmol) and the mixture was stirred under nitrogen at room
temperature.
N-(4-{4-[(6-Butyl-8-quinolinyl)oxy]-1-piperidinyl}butyl)ethanesulfonamide
(for example, as prepared for Example 23, preparation A) (56 mg, 0.125
mmol) was added as a solution in DMF (2 ml), and the mixture stirred for
10 min. Methyl iodide (commercially available, for example, from Aldrich)
(17 mg, 0.125 mmol) was added as a solution in DMF (200 μl), and the
reaction was stirred under nitrogen at room temperature for 1.5 h. The
mixture was diluted with methanol and applied to an SCX-2 cartridge (50
g) eluting with methanol, followed by 10% aqueous 0.88 s.g. ammonia in
methanol. The relevant fractions were concentrated, and the residue was
purified by MDAP. The appropriate fractions were combined and
concentrated to give the title compound as the formate salt: LCMS RT=2.68
min, ES+ve m/z 462 (M+H).sup.+. The material was dissolved in methanol
and treated with 1.25 M hydrogen chloride in methanol (0.5 ml, excess).
The volatiles were removed under a stream of nitrogen to give the title
compound (35 mg, 52%): LCMS RT=2.76 min, ES+ve m/z 462 (M+H).sup.+.

[0398]A mixture of 6-pentyl-8-(4-piperidinyloxy)quinoline (for example, as
prepared for Intermediate 8) (62 mg, 0.2 mmol) and
4-[(ethylsulfonyl)amino]butyl ethanesulfonate (for example, as prepared
for Intermediate 40) (80 mg, 0.24 mmol), sodium hydrogen carbonate (120
mg, 1.4 mmol) and sodium iodide (29 mg, 0.19 mmol) in DMF (2 ml) was
heated to 150° C. for 15 min in a Smith Creator® microwave
oven. LCMS analysis showed that reaction was incomplete, so further
4-[(ethylsulfonyl)amino]butyl ethanesulfonate (26 mg, 0.1 mmol) and DMF
(0.5 ml) were added and the mixture was heated for 15 min further at
150° C. in a Smith Creator® microwave oven. LCMS analysis
showed that reaction was still incomplete, so the mixture was transferred
to a flask, diluting with further DMF (2 ml). Further
4-[(ethylsulfonyl)amino]butyl ethanesulfonate (80 mg, 0.29 mmol) and DMF
(1 ml) were added and the mixture was heated to 60° C. for 3 h
under nitrogen. Further 4-[(ethylsulfonyl)amino]butyl ethanesulfonate (82
mg, 0.3 mmol), sodium iodide (60 mg, 0.4 mmol) and DMF (1 ml) were added
and the mixture was heated to 60° C. overnight under nitrogen. The
reaction mixture was concentrated in vacuo. The residue was applied to an
SCX-2 cartridge (20 g) eluting with methanol, followed by 10% aqueous
0.88 s.g. ammonia in methanol. The relevant fractions were concentrated,
and the residue was purified by MDAP. The appropriate fractions were
combined and concentrated to give the title compound as the formate salt:
LCMS RT=2.92 min, ES+ve m/z 462 (M+H).sup.+. The material was dissolved
in methanol and treated with 1.25 M hydrogen chloride in methanol (0.5
ml, excess). The volatiles were removed under a stream of nitrogen to
give the title compound (15 mg, 14%): LCMS RT=2.95 min, ES+ve m/z 462
(M+H).sup.+.

[0410](3-{4-[(6-Butyl-8-quinolinyl)oxy]-1-piperidinyl}propyl)amine (for
example, as prepared for Intermediate 36) (33 mg, 0.1 mmol) was dissolved
in DCM (2 ml), and treated with propyl isocyanate (commercially
available, for example, from Aldrich) (14 μl, 0.15 mmol). The mixture
was stirred at room temperature for 20 min, then left to stand at room
temperature overnight. The reaction mixture was applied to an SCX-2
cartridge (10 g) eluting with methanol, followed by 10% aqueous 0.88 s.g.
ammonia in methanol. The relevant fractions were concentrated, and the
residue was purified by MDAP. The appropriate fractions were combined and
concentrated to give the title compound as the formate salt (34 mg): LCMS
RT=2.76 min, ES+ve m/z 427 (M+H).sup.+. The material was dissolved in
methanol and treated with 1.25 M hydrogen chloride in methanol (0.5 ml,
excess). The volatiles were removed under a stream of nitrogen to give
the title compound (40.5 mg, 81%): LCMS RT=2.78 min, ES+ve m/z 427
(M+H).sup.+.

Biological Assays

[0411]The compounds of the invention may be tested for in vitro and/or in
vivo biological activity in accordance with the following or similar
assays.

H1 receptor cell line generation and FLIPR Assay Protocol

1. Generation of Histamine H1 Cell Line

[0412]The human H1 receptor is cloned using known procedures described in
the literature [Biochem. Biophys. Res. Commun., 201(2):894 (1994)].
Chinese hamster ovary (CHO) cells stably expressing the human H1 receptor
are generated according to known procedures described in the literature
[Br. J. Pharmacol., 117(6):1071 (1996)].

[0415]10 μl of test compound, diluted to the required concentration in
Tyrodes buffer+probenecid (or 10 μl Tyrodes buffer+probenecid as a
control) is added to each well and the plate is incubated for 30 min at
37° C., 5% CO2. The plates are then placed into a FLIPR®
(Molecular Devices, UK) to monitor cell fluorescence (λex=488
nm, λEM=540 nm) in the manner described in Sullivan et al.,
(In: Lambert DG (ed.), Calcium Signaling Protocols, New Jersey: Humana
Press, 1999, 125-136) before and after the addition of 10 μl histamine
at a concentration that results in the final assay concentration of
histamine being EC80.

[0416]Functional antagonism is indicated by a suppression of histamine
induced increase in fluorescence, as measured by the FLIPR® system
(Molecular Devices). By means of concentration effect curves, functional
affinities are determined using standard pharmacological mathematical
analysis.

[0419]The plates are then placed into a FLIPR® (Molecular Devices, UK)
to monitor cell fluorescence (λex=488 nm, λEM=540
nm) in the manner described in Sullivan et al., (In: Lambert DG (ed.),
Calcium Signaling Protocols, New Jersey: Humana Press, 1999, 125-136)
before and after the addition of 50 μl histamine over a concentration
range of 1 mM-0.1 nM. The resultant concentration response curves are
analysed by non-linear regression using a standard four parameter
logistic equation to determine the histamine EC50, the concentration
of histamine required to produce a response of 50% of the maximum
response to histamine. The antagonist pA2 is calculated using the
following standard equation: pA2=log(DR-1)-log[ B] where DR=dose ratio,
defined as EC50antagonist-treated/EC50control and
[B]=concentration of antagonist.

[0420]To determine the antagonist duration, cells are cultured overnight
in non-coated black-walled clear bottom 96-well tissue culture plates,
are washed with PBS and are incubated with a concentration of antagonist
chosen to give an approximate DR in the range 30-300. Following the 30
min antagonist incubation period, the cells are washed two or three times
with 200 μl of PBS and then 100 μl Tyrodes buffer is added to each
well to initiate antagonist dissociation. Following incubation for
predetermined times, typically 30-270 min at 37° C., the cells are
then washed again with 200 μl PBS and are incubated with 100 μl
Tyrodes buffer containing Brilliant Black, probenecid and Fluo-4 for 45
min at 37° C., as described above. After this period, the cells
are challenged with histamine in the FLIPR® as described above. The
dose ratio at each time point is used to determine the fractional H1
receptor occupancy by the following equation: fractional receptor
occupancy=(DR-1)/DR. The decrease in receptor occupancy over time
approximates to a straight line and is analysed by linear regression. The
slope of this straight line fit is used as an index of the dissociation
rate of the antagonist. The dose ratios for antagonist treated cells and
for antagonist treated and washed cells at each time point are used to
calculate a relative dose ratio (rel DR) which is also used as an index
of antagonist duration. Antagonists with long duration of action produce
rel DR values close to 1, and antagonists with short duration of action
produce rel DR values that approaches the dose ratio value obtained for
antagonist treatment alone.

[0421]The histamine H3 cDNA is isolated from its holding vector, pCDNA3.1
TOPO (InVitrogen), by restriction digestion of plasmid DNA with the
enzymes BamH1 and Not-1 and is ligated into the inducible expression
vector pGene (InVitrogen) digested with the same enzymes. The
GeneSwitch® system (a system where in transgene expression is switched
off in the absence of an inducer and switched on in the presence of an
inducer) is performed as described in U.S. Pat. Nos. 5,364,791;
5,874,534; and 5,935,934. Ligated DNA is transformed into competent
DH5α E. coli host bacterial cells and is plated onto Luria Broth
(LB) agar containing Zeocin® (an antibiotic which allows the selection
of cells expressing the sh ble gene which is present on pGene and
pSwitch) at 50 μgml-1. Colonies containing the re-ligated plasmid
are identified by restriction analysis. DNA for transfection into
mammalian cells is prepared from 250 ml cultures of the host bacterium
containing the pGeneH3 plasmid and is isolated using a DNA preparation
kit (Qiagen Midi-Prep) as per manufacturers guidelines (Qiagen).

[0423]10-14 days post selection, 10 nM Mifepristone (InVitrogen) is added
to the culture medium to induce the expression of the receptor. 18 h post
induction, cells are detached from the flask using ethylenediamine
tetra-acetic acid (EDTA; 1:5000; InVitrogen), following several washes
with PBS, pH 7.4 and are resuspended in Sorting Medium containing Minimum
Essential Medium (MEM), without phenol red, and are supplemented with
Earles salts and 3% Foetal Clone II (Hyclone). Approximately
1×107 cells are examined for receptor expression by staining
with a rabbit polyclonal antibody, 4a, raised against the N-terminal
domain of the histamine H3 receptor, are incubated on ice for 60 min,
followed by two washes in sorting medium. Receptor bound antibody is
detected by incubation of the cells for 60 min on ice with a goat anti
rabbit antibody, conjugated with Alexa 488 fluorescence marker (Molecular
Probes). Following two further washes with Sorting Medium, cells are
filtered through a 50 μm Filcon® (BD Biosciences) and then are
analysed on a FACS Vantage SE Flow Cytometer fitted with an Automatic
Cell Deposition Unit. Control cells are non-induced cells treated in an
analogous manner. Positively stained cells are sorted as single cells
into 96-well plates, containing Complete Medium containing 500
μgml-1 Zeocin® and are allowed to expand before reanalysis for
receptor expression via antibody and ligand binding studies. One clone,
3H3, is selected for membrane preparation.

Membrane Preparation from Cultured Cells

[0424]All steps of the protocol are carried out at 4° C. and with
pre-cooled reagents. The cell pellet is resuspended in 10 volumes of
homogenisation buffer (50 mM
N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid (HEPES), 1 mM
ethylenediamine tetra-acetic acid (EDTA), pH 7.4 with KOH, supplemented
with 10-6 M leupeptin (acetyl-leucyl-leucyl-arginal; Sigma L2884),
25 μgml-1 bacitracin (Sigma B0125), 1 mM phenylmethylsulfonyl
fluoride (PMSF) and 2×10-6 M pepstain A (Sigma)). The cells
are then homogenised by 2×15 second bursts in a 1 litre glass
Waring blender, followed by centrifugation at 500 g for 20 min. The
supernatant is then spun at 48,000 g for 30 min. The pellet is
resuspended in homogenisation buffer (4× the volume of the original
cell pellet) by vortexing for 5 sec, followed by homogenisation in a
Dounce homogeniser (10-15 strokes). At this point the preparation is
aliquoted into polypropylene tubes and stored at -80° C.

Histamine H3 Functional Antagonist Assay

[0425]For each compound being assayed, in a solid white 384 well plate, is
added:--

[0426]After 2-6 h, the plate is centrifuged for 5 min at 1500 rpm and
counted on a Viewlux counter using a 613/55 filter for 5 minplate-1.
Data is analysed using a 4-parameter logistic equation. Basal activity is
used as minimum, i.e. histamine not added to well.

Intranasal Challenge Method: Whole Body Plethysmography

(a) Sensitisation

[0427]Female Dunkin-Hartley guinea pigs 150-250 g are sensitised twice
daily for 5 days (week 1) with ovalbumin (OVA) and aluminium hydroxide
(Al(OH)3 or Alum) in physiological saline, 25 μl/nostril.
Solution is made up at 20 μg/ml OVA, 180 mg/ml Alum. During weeks 2
and 3 animals receive 25 μl/nostril of OVA (5 mg/ml) once daily.
During Week 4 guinea pigs will be entered into study but are continually
sensitized as per weeks 2 and 3 until the day before dosing with compound
or vehicle.

(b) Compound Vehicle Pretreatment

[0428]Pretreatment with test compound is performed at various times prior
to histamine challenge. Efficacy dose-response curves are determined 1 hr
and/or 3 hr after dosing whereas duration of action may be studied up to
7 days post dose (for example, at 24 hours). Test compounds are
formulated as solutions in 0.9% sterile saline or suspensions in 0.9%
sterile saline/tween80.

[0429]Guinea pigs were anaesthetised with isoflurane (5%, 2-31/min
O2), placed in a supine position, and 25 μl of test compound or
vehicle dosed into each nostril using a Gilson pipette. After dosing,
animals remain supine for at least 30 seconds (e.g. 60 seconds) during
recovery from anaesthesia.

(c) Histamine Challenge Protocol

[0430]At 30 minutes before the time of histamine challenge, guinea pigs
are dosed with atropine sulphate (Sigma A0257, dissolved in saline), 1
mg/kg i.p. Animals are then placed into whole body plethysmograph systems
(Buxco® Electronics) where the parameter PenH area under curve (AUC)
is recorded as outlined in Hamelmann, E., Schwarze, J., Takeda, K.,
Oshiba, A., Larsen, L., Irvin, C. G. & Gelfand, E. W. (1997), Noninvasive
measurement of airway responsiveness in allergic mice using barometric
plethysmography., Am. J. Respir. Crit. Care Med., 156, 766-775. A 10
minute baseline AUC is recorded and if this value is over 1000, the
animals are excluded.

[0431]After the stipulated pre-dose time has been reached, guinea pigs are
re-anaesthetised with isoflurane and dosed with either 10 mM or 15 mM
histamine or phosphate-buffered saline (PBS), (25 μl per nostril). On
recovery from anaesthesia animals are returned to the individual
plethysmograph chambers and 4×10 min consecutive PenH AUC
recordings are made. These recordings are summed to give a cumulative AUC
over 40 mins post histamine challenge for each animal. Data are analysed
using ANOVA with post-hoc Fishers LSD test (general linear models,
Statistica®) and finally Hochberg adjustment. Inhibition of
histamine-induced congestion is determined by statistically significant
differences between the mean responses of compound pre-treated groups
compared to the vehicle pre-treated, histamine-challenged group.

CNS Penetration

(i) CNS Penetration by Bolus Administration

[0432]Compounds are dosed intravenously at a nominal dose level of 1
mgkg-1 to male CD Sprague Dawley rats. Compounds are formulated in
5% DMSO/45% PEG200/50% water. Blood samples are taken under terminal
anaesthesia with isoflurane at 5 min post-dose and the brains are also
removed for assessment of brain penetration. Blood samples are taken
directly into heparinised tubes. Blood samples are prepared for analysis
using protein precipitation and brain samples are prepared using
extraction of drug from brain by homogenisation and subsequent protein
precipitation. The concentration of parent drug in blood and brain
extracts is determined by quantitative LC-MS/MS analysis using
compound-specific mass transitions.

(ii) CNS Penetration Following Intravenous Infusion at Steady State

[0433]A loading dose of the compounds is given to male CD Sprague Dawley
rats at a nominal dose level of 0.4 mgkg-1. The compounds are then
infused intravenously for 4 h at a nominal dose level of 0.1
mgkg-1h-1. Compounds are formulated in 2% DMSO/30% PEG200/68%
water. Serial or terminal blood samples are taken at 0.5, 1.5, 2.5, 3,
3.5 and 4 h post dose. The final blood sample is collected under terminal
anaesthesia with isoflurane and the brains are also removed for
assessment of brain penetration. Blood samples are taken directly into
heparinised tubes. Blood samples are prepared for analysis using protein
precipitation and brain samples are prepared using extraction of drug
from brain by homogenisation and subsequent protein precipitation. The
concentration of parent drug in blood and brain extracts is determined by
quantitative LC-MS/MS analysis using compound-specific mass transitions.

Results

[0434]The compounds of Examples 1 to 36 were tested in the above or
similar assays/methods and showed:

(i) Examples 1, 13, 14, 15 and 16 had an average pKi (pKb) at H1
of approximately greater than 7. The remaining Examples had an average
pKi (pKb) at H1 of approximately greater than 8.Examples 8, 12
and 13 had average pA2 values of greater than approximately 7. Examples
1, 3, 9, 10, 14, 15, 16, 17, 25, 28, 29, 33 and 35 had average pA2 values
of greater than approximately 8. Examples 2, 5, 6, 7, 11, 18, 19, 22,
23B, 24, 26, 31, 32, 34 and 36 had average pA2 values of greater than
approximately 9.(ii) The compounds of the Examples had an average
pKi (pKb) at H3 of less than 6.5.(iii) The compounds of Example
4A and Example 23B demonstrated low CNS penetration.(iv) Compound of
Examples 4B, 23, 24 and 26 exhibited at one or more time points a longer
duration of action than azelastine in the histamine H1 functional
antagonist assay. Other compounds were either not tested or were tested
and did not exhibit a longer duration of action.(v) In the intranasal
challenge model, compound of Example 23B dosed intranasally at 1 mg/ml
either 3 hr or 24 hr before histamine challenge significantly (p<0.05)
inhibited the response at both timepoints. In the same model, azelastine
failed to show a similar duration of action when administered at the same
concentration.

Example Compositions

[0435]The aqueous pharmaceutical compositions of the invention may be
prepared according to the following general method:

[0436]Where appropriate, the isotonicity adjusting agent(s) is charged
into a suitable mixing vessel containing purified water and dissolved
with stirring.

[0437]The suspending/thickening agent(s) is then charged into the mixing
vessel and dispersed throughout the solution. The resulting suspending
vehicle is allowed to hydrate for an appropriate period of time to ensure
cross-linkage and gelation, which may take 60 minutes or longer.

[0438]Preservative(s) is pre-dissolved in purified water in a separate
vessel, optionally with heating, for example to 50-60° C.
depending on the preservative chosen, to aid dissolution, and then added
to the thickened isotonicity adjusting agent(s) solution with continuous
stirring.

[0439]Buffering agents, if included, are dissolved in a minimum amount of
purified water, optionally heated, for example to about 50-60° C.
as appropriate depending on the buffering agents chosen, and stirred to
dissolve in separate containers. The separate solutions are combined,
mixed well and then added to the bulk solution with continuous stirring.

[0440]In a separate mixing vessel, the wetting agent(s) is mixed with
purified water which optionally may be heated, for example to about
50-60° C. as appropriate depending on the wetting agent(s) chosen,
and stirred to dissolve. A slurry or solution of active compound(s) is
then prepared by adding the resultant wetting agent(s) solution to the
active compound(s), which may be particle size reduced for example
micronised, and mixed prior to homogenising/refining.

[0441]Additionally, in a separate mixing vessel, additional
preservative(s), if needed, may be mixed with purified water and stirred
to dissolve.

[0442]Following the dispersion and refining of the slurry/solution of
active compound(s) it is added to the mixing vessel containing the
suspending/thickening agent and dispersed with stirring. Following the
addition of the slurry of active compound(s), any additional preservative
may be added to the bulk suspension/solution and dispersed with
continuous stirring. Finally, the suspension is made to its final mass by
adding water and stirred.

[0443]Co-solvent(s), if included, may be added before or after the
addition of the buffering agents. Alternatively, the co-solvent(s) may be
added during the formation of the drug slurry or solution.

[0444]Preservative(s), if included, may be added before or after the
addition of the suspending/thickening agent(s).

[0445]Fluticasone furoate is used in its unsolvated form as polymorphic
Form 1. The preparation of fluticasone furoate
(6α,9α-difluoro-17α-[(2-furanylcarbonyl)oxy]-11β-h-
ydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioic acid
S-fluoromethyl ester), solvates and polymorphs thereof including
polymorphic Form 1, and biological activity thereof, are disclosed in
International Patent Application WO02/12265 and International Patent
Application WO03/066024 incorporated fully herein by reference.

[0446]N-(4-{4-[(6-butyl-8-quinolinyl)oxy]-1-piperidinyl}butyl)ethanesulfon-
amide is used in the form of the dihydrochloride salt, optionally as
polymorphic form 1.

Example Composition 1 May be Made According to the Following Procedure

[0447]Approximately 200 mL of water is added to a tared beaker. The
xyltiol is added with stirring (Silverson mixer) until dissolved. In a
separate vessel, the EDTA is dissolved in approximately 5 mL, using heat
(without boiling) to aid dissolution. The EDTA solution is then added to
the xylitol solution. With mixing (Silverson mixer), the Avicel® CL611
is added to the xylitol and EDTA solution. The speed of the mixer is
adjusted, as required, to maintain a vortex. After addition of the
Avicel® CL611, and once it is well dispersed, the mixture is allowed
to stand for at least 60 minutes to ensure hydration of the Avicel®
CL611. In one vessel, the citric acid is dissolved in approximately 10 mL
of water, and, in another vessel, the sodium citrate is dissolved in 10
mL of water. The vessels are heated with stirring (without boiling) to
aid dissolution. Once the citric acid and sodium citrate are dissolved,
they are combined and mixed thoroughly. The buffer is then added to the
bulk suspension with mixing (Silverson mixer). In another vessel, the
polysorbate 80 is dissolved in approximately 10 mL of water with heat and
stirring (without boiling) to aid dissolution. The propylene glycol is
added to the polysorbate 80 solution. To
N-(4-{4-[(6-butyl-8-quinolinyl)oxy]-1-piperidinyl}butyl)ethanesulfonamide
(in the form of the dihydrochloride salt) is added approximately 3-5 mL
of the propylene glycol and polysorbate 80 solution. The drug substance
is wetted by mixing with a spatula or alternatively placing in a sealed
container and shaking on a shaker until all the drug is wetted. The drug
mixture is homogenised (small Silverson head or small Ultra Turrax) to
disperse and/or dissolve the drug substance for approximately 2-3
minutes. The drug mixture is added to the bulk suspension and mixed
(Silverson mixer). Any remaining polysorbate 80 solution and propylene
glycol is added to the bulk suspension. The drug mixture vessel,
polysorbate 80 vessel and propylene glycol vessel are rinsed with water
(small Silveron head or Ultra Turrax) and the rinsings are added to the
bulk solution. In another vessel, the potassium sorbate is dissolved in
approximately 5 mL of water with stirring and heat (without boiling) to
aid dissolution. The potassium sorbate solution is added to the bulk
solution with stirring (Silverson mixer). The tared beaker is made up to
the final weight with water (500 g) and mixed for a further 3 minutes.
The pH is measured (target pH=4.5, with limits of 4.0 to 5.0).

[0448]In Example Compositions 1 to 8, the concentration of micronised
N-(4-{4-[(6-butyl-8-quinolinyl)oxy]-1-piperidinyl}butyl)ethanesulfonamide
is given as the free base, which concentrations are 0.025% (w/w), 0.05%
(w/w), 0.1% (w/w), 0.25% (w/w), 0.5% (w/w) and 0.9% (w/w), based on the
total weight of the composition.

[0449]It will be appreciated that
N-(4-{4-[(6-butyl-8-quinolinyl)oxy]-1-piperidinyl}butyl)ethanesulfonamide
may be used in the form of a pharmaceutically acceptable salt at an
appropriate concentration, depending on the salt chosen, such as to
provide the desired concentration of free base.

[0450]Example compositions may be filled into suitable containers
depending on the chosen route of administration. For intransal
administration, suitable containers are described hereinabove and
typically are made of plastics and dispense 50 to 100 μL of
composition per actuation.